Ⅰ型干扰素和分泌IL-10的B细胞对新生期炎症反应的负调控
摘要
前言
新生期(neonatal period)指的是动物刚出生后的一段时间,人类为0至28天,而小鼠为0至7天。新生期动物的一大特征是对病原微生物高度易感,获得性免疫应答(adaptive immune response)表现为抗体应答水平低,T细胞免疫通常偏向Th2途径。获得性免疫应答低下被认为是新生期动物对病原微生物高度易感一个因素,但其重要性及是否存在其它机制尚有待于进一步阐明。天然免疫(innate immunity)是抵抗外源微生物入侵的第一道防线,在抗感染免疫的早期起关键作用,同时天然免疫处于获得性免疫的上游,不但为激活获得性免疫所必需,而且决定获得性免疫的方向和强度。天然免疫的启动是天然免疫细胞通过模式识别受体识别病原微生物中保守的分子配体而实现的,其中Toll样受体(Toll-like receptor,TLR)是最重要的一类受体。目前对新生期天然免疫的研究较少,且缺乏系统性,新生期天然免疫功能是否正常还存有争议。本文以新生期小鼠为研究对象,应用体内和体外实验对新生期天然免疫系统进行了比较全面的研究,证明了新生期天然免疫细胞在TLR配体的刺激下功能正常,揭示了CD5~+ B细胞对其它天然免疫细胞炎性应答负调控的新机制,该机制为新生期动物对病原微生物高度敏感的原因提供了新的可能解释。
1新生期小鼠对TLR配体的炎性应答
首先测定了新生期小鼠在注射TLR配体后体内的炎性应答,同时以成年鼠组作为对照。注射TLR9配体CpG后,从成年鼠的脾脏和肝脏中可检测出高水平的炎性细胞因子(TNF-α,IL-1β,IL-6和IL-12),而在新生期小鼠的相应器官未能或仅能检测到很低水平的炎性细胞因子。与此对应的是,绝大多数成年鼠死于D-氨基半乳糖(D-galactosamine)预致敏的、CpG诱导的炎症反应,而新生期小鼠却在攻击后存活。采用其它TLR配体(Pam3CSK4[TLR2-L],Poly I:C[TLR3-L],LPS[TLR4-L]和R848[TLR7-L])也得到类似的结果,这说明与成年鼠相比,新生期小鼠在体内炎性应答方面存在缺陷。在本实验条件下,炎性细胞因子主要由天然免疫系统的树突细胞(dendriticcells,DC)和CDl1b~+體系细胞(myeloid cells,包括单核细胞,巨噬细胞,粒细胞等)产生。为研究新生期小鼠的这些天然免疫细胞是否存在功能上的缺陷,采用胞内细胞因子染色或纯化细胞的方法,测定了新生期常规树突细胞(conventional dendritic cells,cDC)、浆细胞样树突细胞(plasmacytoid dendritic cells,pDC)和CDl1b~+髓系细胞在TLR配体刺激下分泌炎性细胞因子的能力。结果在这些体外试验中发现,与成年鼠相比,新生期天然免疫细胞功能上并不存在缺陷,刺激后可分泌正常水平的炎性细胞因子。
白介素10(interleukin 10,IL-10)是最重要的炎性负调节分子之一。在CpG诱导的休克模型中,IL-10缺失的新生期小鼠显示与野生型成年鼠相似的高敏感性,并在体内产生高水平的炎性细胞因子,这说明在新生期这个阶段,小鼠在体内炎症诱导方面不存在发育上的缺陷。
以上结果提示:新生期小鼠天然免疫细胞本身功能正常,但在体内存在着对这些天然免疫细胞炎性反应的负调节机制,并且IL-10可能起关键作用。
2新生期CD5~+ B细胞对新生期小鼠炎症反应的抑制
IL-10缺失的新生期小鼠对CpG的高敏感性说明了体内产生的IL-10对炎性反应控制的重要性。前期的研究发现,在CpG刺激下,小鼠新生期CD5~+ B细胞是抗炎细胞因子IL-10的主要来源。新生期CD5~+ B细胞占全部B细胞的15%～30%,而这类细胞在成年鼠B细胞中的比例小于2%。除CpG外,CD5~+ B细胞也在其它TLR配体Pam3CSK4,LPS和R848刺激下产生大量的IL-10。体外共培养试验证明,来自于CD5~+ B细胞的IL-10抑制了新生期cDC,pDC和CD11b~+體系细胞等天然免疫细胞分泌炎性细胞因子的能力,而且这种抑制不依赖于细胞间的直接接触。
分泌IL-10的CD5~+ B细胞抑制新生期炎性应答的重要性进一步在体内实验中得到证实。B细胞或CD5~+ B细胞缺失的新生期小鼠在注射CpG后,体内的炎性细胞因子水平上升,并且恢复了对D-氨基半乳糖预致敏的休克模型的敏感性。在预先接受新生期B细胞或CD5~+ B细胞输注后,IL-10缺失或B细胞缺失的新生期小鼠能够免于CpG诱导的休克反应。因此,分泌IL-10的CD5~+ B细胞在体内控制了新生期小鼠的炎症反应。
3Ⅰ型干扰素通过分泌IL-10的CD5~+ B细胞控制新生期炎症反应
在新生期小鼠pDC与CD5~+ B细胞的共培养试验中发现,在CpG和R848刺激下,除了B细胞产生的IL-10显著抑制了pDC分泌Ⅰ型干扰素(IFN-α和IFN-β)和其它炎性细胞因子外,CD5~+ B细胞产生的IL-10显著高于CD5~+ B细胞单独培养时产生的水平。这说明pDC促进了B细胞IL-10的分泌。在所测定的pDC产生的细胞因子中,只有IFN-α和IFN-β显著提高CpG刺激下新生期B细胞IL-10的分泌。当pDC与Ⅰ型干扰素受体缺失的新生期B细胞共培养时,pDC失去增强新生期B细胞分泌IL-10的能力,证实pDC产生的Ⅰ型干扰素是促进B细胞IL-10产生的关键分子。cDC和體系细胞以相同的机制通过分泌Ⅰ型干扰素来增加B细胞IL-10的产生。
为进一步研究Ⅰ型干扰素在新生期炎性应答中的作用,测定了Ⅰ型干扰素受体缺失的小鼠体内的炎性应答。与野生型新生期小鼠相比,Ⅰ型干扰素受体缺失的新生期小鼠在注射CpG后产生明显的炎症反应,并且恢复对D-氨基半乳糖预致敏的休克模型的敏感性。相反的现象却出现在成年鼠,Ⅰ型干扰素受体缺失的成年鼠比正常对照组产生显著减弱的炎症反应,并且对CpG引发的休克模型不敏感。这说明Ⅰ型干扰素在成年期促进而在新生期抑制炎症反应。
Ⅰ型干扰素在新生期对炎症反应的抑制依赖于CD5~+ B细胞和IL-10的存在,因为在缺乏CD5~+ B细胞或IL-10的情况下,Ⅰ型干扰素促进新生期炎性应答。研究发现只有野生型新生期小鼠B细胞,而不是Ⅰ型干扰素受体缺失的新生期小鼠B细胞可以保护IL-10缺失的新生期小鼠免于CpG诱导的致死性休克,从而进一步说明Ⅰ型干扰素在体内通过增强B细胞产生ILL-10来控制新生期小鼠的炎症反应。
结论
新生期属于一个特别的时期,一方面,生长代谢旺盛且许多器官的发育还不完善,需要一个稳定的生长环境。许多研究表明,这个时期的炎症反应将导致生长发育迟缓,严重的可导致死亡。新生期面对大量的外源微生物,需要迅速建立针对这些炎症诱导物的耐受,以维持内环境的稳定。另一方面,新生期的炎症反应应答低下将导致不能有效清除病原微生物,从而造成对病原微生物的高度敏感。本研究表明,新生期小鼠的天然免疫细胞在功能上不存在缺陷,在TLR配体的刺激后可产生正常的炎性应答,但是这种能力在体内却被一群分泌IL-10,具有负调节功能的CD5~+ B细胞亚群所控制,这种控制是受发育调控的,因为新生期是CD5~+ B细胞亚群发生的高峰期,随着小鼠的生长,CD5~+ B细胞的产生逐渐减少。另一个重要的发现是,Ⅰ型干扰素显著增加CD5~+ B细胞IL-10的分泌,而且在体内CD5~+ B细胞负调节作用依赖于Ⅰ型干扰素的存在,揭示了炎性应答启动后机体的一种负反馈调节机制。因此,Ⅰ型干扰素及分泌IL-10的CD5~+ B细胞对体内炎症反应的控制保证了小鼠在新生期生长发育环境的稳定,但另一方面也可能会导致它们对病原微生物抵抗力的下降。
Neonates show high susceptibility to infections and develop poor immune responses.To determine whether these phenomena are linked to a dysfunction of neonatal innate immunity, we have systematically studied the innate proinflammatory responses in neonatal mice following TLR ligand stimulation.
We first found that neonatal mice poorly develop inflammatory responses in vivo to TLR agonists as compared to adult mice.However,in vitro,neonatal cDC,pDC and CD11b~+ myeloid cells are functionally competent and produce high levels of proinflammatory cytokines after TLR triggering.It appears that in vivo TLR agonists also activate CD5~+ B cells to produce IL-10.Neonates deficient for CD5~ B cells or IL-10 showed higher proinflammatory responses and become lethally susceptible to inflammation triggered by CpG challenge.Transfer of total neonatal B cells,or CD5~+ B cells,but not CD5 B cells nor IL-10~(-/-) B cells can rescue these mice from lethal inflammation.
We next studied the role of type I IFNs in neonatal inflammation.Following CpG injection, typeⅠIFNs are required to develop the inflammatory responses in adult mice whereas they negatively control neonatal acute inflammation through IL-10 producing B cells.Wild type, but not typeⅠIFN-deficient neonatal B cells could rescue IL-10~(-/-) neonates from a lethal CpG challenge.
Altogether,these data reveal a negative regulatory mechansim for the control of neonatal inflammation exerted by IL-10 producing CD5~+ B cells and typeⅠIFNs following TLR activation.The increased number of CD5~+ B cells at neonatal stage as compared to adult suggests that this regulation is developmentally regulated.This negative control of inflammation at the systemic level can be seen as beneficial for the neonates to maintain a harmless environment for normal development in inflammatory conditions,but on the other hand,it may contribute to the high susceptibility of neonates to viral or bacterial infections.
新生期(neonatal period)指的是动物刚出生后的一段时间,人类为0至28天,而小鼠为0至7天。新生期动物的一大特征是对病原微生物高度易感,获得性免疫应答(adaptive immune response)表现为抗体应答水平低,T细胞免疫通常偏向Th2途径。获得性免疫应答低下被认为是新生期动物对病原微生物高度易感一个因素,但其重要性及是否存在其它机制尚有待于进一步阐明。天然免疫(innate immunity)是抵抗外源微生物入侵的第一道防线,在抗感染免疫的早期起关键作用,同时天然免疫处于获得性免疫的上游,不但为激活获得性免疫所必需,而且决定获得性免疫的方向和强度。天然免疫的启动是天然免疫细胞通过模式识别受体识别病原微生物中保守的分子配体而实现的,其中Toll样受体(Toll-like receptor,TLR)是最重要的一类受体。目前对新生期天然免疫的研究较少,且缺乏系统性,新生期天然免疫功能是否正常还存有争议。本文以新生期小鼠为研究对象,应用体内和体外实验对新生期天然免疫系统进行了比较全面的研究,证明了新生期天然免疫细胞在TLR配体的刺激下功能正常,揭示了CD5~+ B细胞对其它天然免疫细胞炎性应答负调控的新机制,该机制为新生期动物对病原微生物高度敏感的原因提供了新的可能解释。
1新生期小鼠对TLR配体的炎性应答
首先测定了新生期小鼠在注射TLR配体后体内的炎性应答,同时以成年鼠组作为对照。注射TLR9配体CpG后,从成年鼠的脾脏和肝脏中可检测出高水平的炎性细胞因子(TNF-α,IL-1β,IL-6和IL-12),而在新生期小鼠的相应器官未能或仅能检测到很低水平的炎性细胞因子。与此对应的是,绝大多数成年鼠死于D-氨基半乳糖(D-galactosamine)预致敏的、CpG诱导的炎症反应,而新生期小鼠却在攻击后存活。采用其它TLR配体(Pam3CSK4[TLR2-L],Poly I:C[TLR3-L],LPS[TLR4-L]和R848[TLR7-L])也得到类似的结果,这说明与成年鼠相比,新生期小鼠在体内炎性应答方面存在缺陷。在本实验条件下,炎性细胞因子主要由天然免疫系统的树突细胞(dendriticcells,DC)和CDl1b~+體系细胞(myeloid cells,包括单核细胞,巨噬细胞,粒细胞等)产生。为研究新生期小鼠的这些天然免疫细胞是否存在功能上的缺陷,采用胞内细胞因子染色或纯化细胞的方法,测定了新生期常规树突细胞(conventional dendritic cells,cDC)、浆细胞样树突细胞(plasmacytoid dendritic cells,pDC)和CDl1b~+髓系细胞在TLR配体刺激下分泌炎性细胞因子的能力。结果在这些体外试验中发现,与成年鼠相比,新生期天然免疫细胞功能上并不存在缺陷,刺激后可分泌正常水平的炎性细胞因子。
白介素10(interleukin 10,IL-10)是最重要的炎性负调节分子之一。在CpG诱导的休克模型中,IL-10缺失的新生期小鼠显示与野生型成年鼠相似的高敏感性,并在体内产生高水平的炎性细胞因子,这说明在新生期这个阶段,小鼠在体内炎症诱导方面不存在发育上的缺陷。
以上结果提示:新生期小鼠天然免疫细胞本身功能正常,但在体内存在着对这些天然免疫细胞炎性反应的负调节机制,并且IL-10可能起关键作用。
2新生期CD5~+ B细胞对新生期小鼠炎症反应的抑制
IL-10缺失的新生期小鼠对CpG的高敏感性说明了体内产生的IL-10对炎性反应控制的重要性。前期的研究发现,在CpG刺激下,小鼠新生期CD5~+ B细胞是抗炎细胞因子IL-10的主要来源。新生期CD5~+ B细胞占全部B细胞的15%～30%,而这类细胞在成年鼠B细胞中的比例小于2%。除CpG外,CD5~+ B细胞也在其它TLR配体Pam3CSK4,LPS和R848刺激下产生大量的IL-10。体外共培养试验证明,来自于CD5~+ B细胞的IL-10抑制了新生期cDC,pDC和CD11b~+體系细胞等天然免疫细胞分泌炎性细胞因子的能力,而且这种抑制不依赖于细胞间的直接接触。
分泌IL-10的CD5~+ B细胞抑制新生期炎性应答的重要性进一步在体内实验中得到证实。B细胞或CD5~+ B细胞缺失的新生期小鼠在注射CpG后,体内的炎性细胞因子水平上升,并且恢复了对D-氨基半乳糖预致敏的休克模型的敏感性。在预先接受新生期B细胞或CD5~+ B细胞输注后,IL-10缺失或B细胞缺失的新生期小鼠能够免于CpG诱导的休克反应。因此,分泌IL-10的CD5~+ B细胞在体内控制了新生期小鼠的炎症反应。
3Ⅰ型干扰素通过分泌IL-10的CD5~+ B细胞控制新生期炎症反应
在新生期小鼠pDC与CD5~+ B细胞的共培养试验中发现,在CpG和R848刺激下,除了B细胞产生的IL-10显著抑制了pDC分泌Ⅰ型干扰素(IFN-α和IFN-β)和其它炎性细胞因子外,CD5~+ B细胞产生的IL-10显著高于CD5~+ B细胞单独培养时产生的水平。这说明pDC促进了B细胞IL-10的分泌。在所测定的pDC产生的细胞因子中,只有IFN-α和IFN-β显著提高CpG刺激下新生期B细胞IL-10的分泌。当pDC与Ⅰ型干扰素受体缺失的新生期B细胞共培养时,pDC失去增强新生期B细胞分泌IL-10的能力,证实pDC产生的Ⅰ型干扰素是促进B细胞IL-10产生的关键分子。cDC和體系细胞以相同的机制通过分泌Ⅰ型干扰素来增加B细胞IL-10的产生。
为进一步研究Ⅰ型干扰素在新生期炎性应答中的作用,测定了Ⅰ型干扰素受体缺失的小鼠体内的炎性应答。与野生型新生期小鼠相比,Ⅰ型干扰素受体缺失的新生期小鼠在注射CpG后产生明显的炎症反应,并且恢复对D-氨基半乳糖预致敏的休克模型的敏感性。相反的现象却出现在成年鼠,Ⅰ型干扰素受体缺失的成年鼠比正常对照组产生显著减弱的炎症反应,并且对CpG引发的休克模型不敏感。这说明Ⅰ型干扰素在成年期促进而在新生期抑制炎症反应。
Ⅰ型干扰素在新生期对炎症反应的抑制依赖于CD5~+ B细胞和IL-10的存在,因为在缺乏CD5~+ B细胞或IL-10的情况下,Ⅰ型干扰素促进新生期炎性应答。研究发现只有野生型新生期小鼠B细胞,而不是Ⅰ型干扰素受体缺失的新生期小鼠B细胞可以保护IL-10缺失的新生期小鼠免于CpG诱导的致死性休克,从而进一步说明Ⅰ型干扰素在体内通过增强B细胞产生ILL-10来控制新生期小鼠的炎症反应。
结论
新生期属于一个特别的时期,一方面,生长代谢旺盛且许多器官的发育还不完善,需要一个稳定的生长环境。许多研究表明,这个时期的炎症反应将导致生长发育迟缓,严重的可导致死亡。新生期面对大量的外源微生物,需要迅速建立针对这些炎症诱导物的耐受,以维持内环境的稳定。另一方面,新生期的炎症反应应答低下将导致不能有效清除病原微生物,从而造成对病原微生物的高度敏感。本研究表明,新生期小鼠的天然免疫细胞在功能上不存在缺陷,在TLR配体的刺激后可产生正常的炎性应答,但是这种能力在体内却被一群分泌IL-10,具有负调节功能的CD5~+ B细胞亚群所控制,这种控制是受发育调控的,因为新生期是CD5~+ B细胞亚群发生的高峰期,随着小鼠的生长,CD5~+ B细胞的产生逐渐减少。另一个重要的发现是,Ⅰ型干扰素显著增加CD5~+ B细胞IL-10的分泌,而且在体内CD5~+ B细胞负调节作用依赖于Ⅰ型干扰素的存在,揭示了炎性应答启动后机体的一种负反馈调节机制。因此,Ⅰ型干扰素及分泌IL-10的CD5~+ B细胞对体内炎症反应的控制保证了小鼠在新生期生长发育环境的稳定,但另一方面也可能会导致它们对病原微生物抵抗力的下降。
Neonates show high susceptibility to infections and develop poor immune responses.To determine whether these phenomena are linked to a dysfunction of neonatal innate immunity, we have systematically studied the innate proinflammatory responses in neonatal mice following TLR ligand stimulation.
We first found that neonatal mice poorly develop inflammatory responses in vivo to TLR agonists as compared to adult mice.However,in vitro,neonatal cDC,pDC and CD11b~+ myeloid cells are functionally competent and produce high levels of proinflammatory cytokines after TLR triggering.It appears that in vivo TLR agonists also activate CD5~+ B cells to produce IL-10.Neonates deficient for CD5~ B cells or IL-10 showed higher proinflammatory responses and become lethally susceptible to inflammation triggered by CpG challenge.Transfer of total neonatal B cells,or CD5~+ B cells,but not CD5 B cells nor IL-10~(-/-) B cells can rescue these mice from lethal inflammation.
We next studied the role of type I IFNs in neonatal inflammation.Following CpG injection, typeⅠIFNs are required to develop the inflammatory responses in adult mice whereas they negatively control neonatal acute inflammation through IL-10 producing B cells.Wild type, but not typeⅠIFN-deficient neonatal B cells could rescue IL-10~(-/-) neonates from a lethal CpG challenge.
Altogether,these data reveal a negative regulatory mechansim for the control of neonatal inflammation exerted by IL-10 producing CD5~+ B cells and typeⅠIFNs following TLR activation.The increased number of CD5~+ B cells at neonatal stage as compared to adult suggests that this regulation is developmentally regulated.This negative control of inflammation at the systemic level can be seen as beneficial for the neonates to maintain a harmless environment for normal development in inflammatory conditions,but on the other hand,it may contribute to the high susceptibility of neonates to viral or bacterial infections.
引文
[1]Taniguchi T,Takaoka A.A weak signal for strong responses:interferon-alpha/beta revisited.Nat Rev Mol Cell Biol 2001;2:378-386.
[2]Hardy RR.B-1 B cells:development,selection,natural autoantibody and leukemia.Current opinion in immunology 2006;18:547-555.
[3]Kawai T,Akira S.Innate immune recognition of viral infection.Nature immunology 2006;7:131-137.
[4]Adkins B,Leclerc C,Marshall-Clarke S.Neonatal adaptive immunity comes of age.Nature reviews 2004;4:553-564.
[5]Siegrist CA.Neonatal and early life vaccinology.Vaccine 2001;19:3331-3346.
[6]Wu L.T lineage progenitors:the earliest steps en route to T lymphocytes.Current opinion in immunology 2006;18:121-126.
[7]Liu C,Saito F,Liu Z,et al.Coordination between CCR7- and CCR9-mediated chemokine signals in prevascular fetal thymus colonization.Blood 2006;108:2531-2539.
[8]Rossi FM,Corbel SY,Merzaban JS,et al.Recruitment of adult thymic progenitors is regulated by P-selectin and its ligand PSGL-1.Nature immunology 2005;6:626-634.
[9]Pui JC,Allman D,Xu L,et al.Notchl expression in early lymphopoiesis influences B versus T lineage determination.Immunity 1999;11:299-308.
[10]Sambandam A,Maillard I,Zediak VP,et al.Notch signaling controls the generation and differentiation of early T lineage progenitors.Nature immunology 2005;6:663-670.
[11]Carding SR,Egan PJ.Gammadelta T cells:functional plasticity and heterogeneity.Nature reviews 2002;2:336-345.
[12]Konigshofer Y,Chien YH.Gammadelta T cells-innate immune lymphocytes?Current opinion in immunology 2006;18:527-533.
[13]Farrar JD,Asnagli H,Murphy KM.T helper subset development:roles of instruction,selection,and transcription.The Journal of clinical investigation 2002;109:431-435.
[14]Weaver CT,Harrington LE,Mangan PR,et al.Th17:an effector CD4 T cell lineage with regulatory T cell ties.Immunity 2006;24:677-688.
[15]Adkins B,Hamilton K.Freshly isolated,murine neonatal T cells produce IL-4 in response to anti-CD3 stimulation.J Immunol 1992;149:3448-3455.
[16]Ivanov,II,McKenzie BS,Zhou L,et al.The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+T helper cells.Cell 2006;126:1121-1133.
[17]Carrier Y,Yuan J,Kuchroo VK,et al.Th3 cells in peripheral tolerance.I.Induction of Foxp3-positive regulatory T cells by Th3 cells derived from TGF-beta T cell-transgenic mice.J Immunol 2007;178:179-185.
[18]Carrier Y,Yuan J,Kuchroo VK,et al.Th3 cells in peripheral tolerance.II.TGF-beta-transgenic Th3 cells rescue IL-2-deficient mice from autoimmunity.J Immunol 2007;178:172-178.
[19]Adkins B,Bu Y,Guevara P.Murine neonatal CD4+ lymph node cells are highly deficient in the development of antigen-specific Th1 function in adoptive adult hosts.J Immunol 2002;169:4998-5004.
[20]Adkins B,Chun K,Hamilton K,et al.Naive murine neonatal T cells undergo apoptosis in response to primary stimulation.J Immunol 1996;157:1343-1349.
[21]Li L,Lee HH,Bell JJ,et al.IL-4 utilizes an alternative receptor to drive apoptosis of Th1 cells and skews neonatal immunity toward Th2.Immunity 2004;20:429-440.
[22]Gao Q,Chen N,Rouse TM,et al.The role of interleukin-4 in the induction phase of allogeneic neonatal tolerance.Transplantation 1996;62:1847-1854.
[23]Donckier V,Flamand V,Desalle F,et al.IL-12 prevents neonatal induction of transplantation tolerance in mice.European journal of immunology 1998;28:1426-1430.
[24]Adkins B.Developmental regulation of the intrathymic T cell precursor population.J Immunol 1991;146:1387-1393.
[25]Ikuta K,Kina T,MacNeil I,et al.A developmental switch in thymic lymphocyte maturation potential occurs at the level of hematopoietic stem cells.Cell 1990;62:863-874.
[26]Adkins B.Peripheral CD4+ lymphocytes derived from fetal versus adult thymic precursors differ phenotypically and functionally.J Immunol 2003;171:5157-5164.
[27]Marchant A,Goetghebuer T,Ota MO,et al.Newborns develop a Th1-type immune response to Mycobacterium bovis bacillus Calmette-Guerin vaccination.J Immunol 1999;163:2249-2255.
[28]Vekemans J,Amedei A,Ota MO,et al.Neonatal bacillus Calmette-Guerin vaccination induces adult-like IFN-gamma production by CD4+ T lymphocytes.European journal of immunology 2001;31:1531-1535.
[29]Kollmann TR,Reikie B,Blimkie D,et al.Induction of Protective Immunity to Listeria monocytogenes in Neonates.J Immunol 2007;178:3695-3701.
[30]Martinez X,Brandt C,Saddallah F,et al.DNA immunization circumvents deficient induction of T helper type 1 and cytotoxic T lymphocyte responses in neonates and during early life.Proceedings of the National Academy of Sciences of the United States of America 1997;94:8726-8731.
[31]Forsthuber T,Yip HC,Lehmann PV.Induction of TH1 and TH2 immunity in neonatal mice.Science 1996;271:1728-1730.
[32]Sun CM,Deriaud E,Leclerc C,et al.Upon TLR9 signaling,CD5+ B cells control the IL-12-dependent Th1-priming capacity of neonatal DCs.Immunity 2005;22:467-477.
[33]Sakaguchi S,Sakaguchi N,Asano M,et al.Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains(CD25).Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.J Immunol 1995;155:1151-1164.
[34]Fontenot JD,Rasmussen JP,Williams LM,et al.Regulatory T cell lineage specification by the forkhead transcription factor foxp3.Immunity 2005;22:329-341.
[35]Hori S,Nomura T,Sakaguchi S.Control of regulatory T cell development by the transcription factor Foxp3.Science 2003;299:1057-1061.
[36]Fontenot JD,Gavin MA,Rudensky AY.Foxp3 programs the development and function of CD4+CD25+ regulatory T cells.Nature immunology 2003;4:330-336.
[37]Fontenot JD,Dooley JL,Farr AG,et al.Developmental regulation of Foxp3expression during ontogeny.The Journal of experimental medicine 2005;202:901-906.
[38]Kim JM,Rasmussen JP,Rudensky AY.Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice.Nature immunology 2007;8:191-197.
[39]Lahl K,Loddenkemper C,Drouin C,et al.Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease.The Journal of experimental medicine 2007;204:57-63.
[40]Pihlgren M,Tougne C,Bozzotti P,et al.Unresponsiveness to lymphoid-mediated signals at the neonatal follicular dendritic cell precursor level contributes to delayed germinal center induction and limitations of neonatal antibody responses to T- dependent antigens. J Immunol 2003; 170:2824-2832.
[41] Pihlgren M, Friedli M, Tougne C, et al. Reduced ability of neonatal and early-life bone marrow stromal cells to support plasmablast survival. J Immunol 2006;176:165- 172.
[42] Pihlgren M, Tougne C, Schallert N, et al. CpG-motifs enhance initial and sustained primary tetanus-specific antibody secreting cell responses in spleen and bone marrow, but are more effective in adult than in neonatal mice. Vaccine 2003;21:2492-2499.
[43] Gramzinski RA, Millan CL, Obaldia N, et al. Immune response to a hepatitis B DNA vaccine in Aotus monkeys: a comparison of vaccine formulation, route, and method of administration. Molecular medicine (Cambridge, Mass 1998;4:109-118.
[44] Kovarik J, Bozzotti P, Love-Homan L, et al. CpG oligodeoxynucleotides can circumvent the Th2 polarization of neonatal responses to vaccines but may fail to fully redirect Th2 responses established by neonatal priming. J Immunol 1999;162:1611- 1617.
[45] Edwards MS. Complement in neonatal infections: an overview. Pediatric infectious disease 1986;5:S168-170.
[46] Pihlgren M, Fulurija A, Villiers MB, et al. Influence of complement C3 amount on IgG responses in early life: immunization with C3b-conjugated antigen increases murine neonatal antibody responses. Vaccine 2004;23:329-335.
[47] Pihlgren M, Schallert N, Tougne C, et al. Delayed and deficient establishment of the long-term bone marrow plasma cell pool during early life. European journal of immunology 2001;31:939-946.
[48] Mancuso G, Midiri A, Beninati C, et al. Dual role of TLR2 and myeloid differentiation factor 88 in a mouse model of invasive group B streptococcal disease. J Immunol 2004; 172:6324-6329.
[49] Hoffman JA, Mason EO, Schutze GE, et al. Streptococcus pneumoniae infections in the neonate. Pediatrics 2003;112:1095-1102.
[50] Kovarik J, Bozzotti P, Tougne C, et al. Adjuvant effects of CpG oligodeoxynucleotides on responses against T-independent type 2 antigens. Immunology 2001; 102:67-76.
[51] Weller S, Reynaud CA, Weill JC. Vaccination against encapsulated bacteria in humans: paradoxes. Trends in immunology 2005;26:85-89.
[52] Shortman K, Naik SH. Steady-state and inflammatory dendritic-cell development. Nature reviews 2007;7:19-30.
[53] Karsunky H, Merad M, Cozzio A, et al. Flt3 ligand regulates dendritic cell development from Flt3+ lymphoid and myeloid-committed progenitors to Flt3+ dendritic cells in vivo. The Journal of experimental medicine 2003;198:305-313.
[54] D'Amico A, Wu L. The early progenitors of mouse dendritic cells and plasmacytoid predendritic cells are within the bone marrow hemopoietic precursors expressing Flt3. The Journal of experimental medicine 2003; 198:293-303.
[55] Naik SH, Metcalf D, van Nieuwenhuijze A, et al. Intrasplenic steady-state dendritic cell precursors that are distinct from monocytes. Nature immunology 2006;7:663-671.
[56] Cheng P, Nefedova Y, Corzo CA, et al. Regulation of dendritic-cell differentiation by bone marrow stroma via different Notch ligands. Blood 2007;109:507-515.
[57] Olivier A, Lauret E, Gonin P, et al. The Notch ligand delta-1 is a hematopoietic development cofactor for plasmacytoid dendritic cells. Blood 2006;107:2694-2701.
[58] Dontje W, Schotte R, Cupedo T, et al. Delta-like 1-induced Notchl signaling regulates the human plasmacytoid dendritic cell versus T-cell lineage decision through control of GATA-3 and Spi-B. Blood 2006; 107:2446-2452.
[59] Allman D, Dalod M, Asselin-Paturel C, et al. Ikaros is required for plasmacytoid dendritic cell differentiation. Blood 2006; 108:4025-4034.
[60] Wolber FM, Leonard E, Michael S, et al. Roles of spleen and liver in development of the murine hematopoietic system. Experimental hematology 2002;30:1010-1019.
[61] Dakic A, Shao QX, D'Amico A, et al. Development of the dendritic cell system during mouse ontogeny. J Immunol 2004;172:1018-1027.
[62] Sun CM, Fiette L, Tanguy M, et al. Ontogeny and innate properties of neonatal dendritic cells. Blood 2003;102:585-591.
[63] Dadaglio G, Sun CM, Lo-Man R, et al. Efficient in vivo priming of specific cytotoxic T cell responses by neonatal dendritic cells. J Immunol 2002;168:2219-2224.
[64] De Wit D, Olislagers V, Goriely S, et al. Blood plasmacytoid dendritic cell responses to CpG oligodeoxynucleotides are impaired in human newborns. Blood 2004;103:1030-1032.
[65] Aldebert D, Diallo M, Niang M, et al. Differences in circulating dendritic cell subtypes in peripheral, placental and cord blood in African pregnant women. Journal of reproductive immunology 2007 ;73:11-19.
[66] Darmochwal-Kolarz D, Rolinski J, Buczkowski J, et al. CD1c(+) immature myeloid dendritic cells are predominant in cord blood of healthy neonates. Immunology letters 2004;91:71-74.
[67] Levy O, Zarember KA, Roy RM, et al. Selective impairment of TLR-mediated innate immunity in human newborns: neonatal blood plasma reduces monocyte TNF-alpha induction by bacterial lipopeptides, lipopolysaccharide, and imiquimod, but preserves the response to R-848. J Immunol 2004; 173:4627-4634.
[68] Upham JW, Lee PT, Holt BJ, et al. Development of interleukin-12-producing capacity throughout childhood. Infection and immunity 2002;70:6583-6588.
[69] Lu CY, Beller DI, Unanue ER. During ontogeny, la-bearing accessory cells are found early in the thymus but late in the spleen. Proceedings of the National Academy of Sciences of the United States of America 1980;77:1597-1601.
[70] Muthukkumar S, Goldstein J, Stein KE. The ability of B cells and dendritic cells to present antigen increases during ontogeny. J Immunol 2000;165:4803-4813.
[71] Goriely S, Van Lint C, Dadkhah R, et al. A defect in nucleosome remodeling prevents IL-12(p35) gene transcription in neonatal dendritic cells. The Journal of experimental medicine 2004;199:1011-1016.
[72] Gramzinski RA, Doolan DL, Sedegah M, et al. Interleukin-12- and gamma interferon- dependent protection against malaria conferred by CpG oligodeoxynucleotide in mice. Infection and immunity 2001;69:1643-1649.
[73] Karlsson H, Hessle C, Rudin A. Innate immune responses of human neonatal cells to bacteria from the normal gastrointestinal flora. Infection and immunity 2002;70:6688- 6696.
[74] Levy O, Coughlin M, Cronstein BN, et al. The Adenosine System Selectively Inhibits TLR-Mediated TNF-{alpha} Production in the Human Newborn. J Immunol 2006;177:1956-1966.
[75] Gold MC, Donnelly E, Cook MS, et al. Purified neonatal plasmacytoid dendritic cells overcome intrinsic maturation defect with TLR agonist stimulation. Pediatric research 2006;60:34-37.
[76] Salio M, Dulphy N, Renneson J, et al. Efficient priming of antigen-specific cytotoxic T lymphocytes by human cord blood dendritic cells. International immunology 2003;15:1265-1273.
[77]Barrios C,Brandt C,Bemey M,et al.Partial correction of the TH2/TH1 imbalance in neonatal murine responses to vaccine antigens through selective adjuvant effects.European journal of immunology 1996;26:2666-2670.
[78]Kovarik J,Martinez X,Pihlgren M,et al.Limitations of in vivo IL-12supplementation strategies to induce Th1 early life responses to model viral and bacterial vaccine antigens.Virology 2000;268:122-131.
[79]Lotz M,Gutle D,Walther S,et al.Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells.The Journal of experimental medicine 2006;203:973-984.
[80]Genovese F,Mancuso G,Cuzzola M,et al.Role of IL-10 in a neonatal mouse listeriosis model.J Immunol 1999;163:2777-2782.
[81]Ito S,Ishii KJ,Gursel M,et al.CpG oligodeoxynucleotides enhance neonatal resistance to Listeria infection.J Immunol 2005;174:777-782.
[82]Pedras-Vasconcelos JA,Goucher D,Puig M,et al.CpG oligodeoxynucleotides protect newborn mice from a lethal challenge with the neurotropic Tacaribe arenavirus.J Immunol 2006;176:4940-4949.
[83]Hardy RR,Hayakawa K.B cell development pathways.Annual review of immunology 2001;19:595-621.
[84]Montecino-Rodriguez E,Dorshkind K.New perspectives in B-1 B cell development and function.Trends in immunology 2006;27:428-433.
[85]Kearney JF.Innate-like B cells.Springer seminars in immunopathology 2005;26:377-383.
[86]Rumfelt LL,Zhou Y,Rowley BM,et al.Lineage specification and plasticity in CD19-early B cell precursors.The Journal of experimental medicine 2006;203:675-687.
[87]Solvason N,Lehuen A,Keamey JF.An embryonic source of Ly1 but not conventional B cells.International immunology 1991;3:543-550.
[88]Hayakawa K,Hardy RR,Herzenberg LA,et al.Progenitors for Ly-1 B cells are distinct from progenitors for other B cells.The Journal of experimental medicine 1985;161:1554-1568.
[89]Kantor AB,Stall AM,Adams S,et al.Differential development of progenitor activity for three B-cell lineages.Proceedings of the National Academy of Sciences of the United States of America 1992;89:3320-3324.
[90]Hardy RR,Hayakawa K.A developmental switch in B lymphopoiesis.Proceedings of the National Academy of Sciences of the United States of America 1991;88:11550-11554.
[91]Godin IE,Garcia-Porrero JA,Coutinho A,et al.Para-aortic splanchnopleura from early mouse embryos contains B1a cell progenitors.Nature 1993;364:67-70.
[92]Montecino-Rodriguez E,Leathers H,Dorshkind K.Identification of a B-1 B cell-specified progenitor.Nature immunology 2006;7:293-301.
[93]Cong YZ,Rabin E,Wortis HH.Treatment of murine CD5- B cells with anti-Ig,but not LPS,induces surface CD5:two B-cell activation pathways.International immunology 1991;3:467-476.
[94]Wortis HH,Teutsch M,Higer M,et al.B-cell activation by crosslinking of surface IgM or ligation of CD40 involves alternative signal pathways and results in different B-cell phenotypes.Proceedings of the National Academy of Sciences of the United States of America 1995;92:3348-3352.
[95]Berland R,Wortis HH.Origins and functions of B-1 cells with notes on the role of CD5.Annual review of immunology 2002;20:253-300.
[96]Hayakawa K,Asano M,Shinton SA,et al.Positive selection of natural autoreactive B cells.Science 1999;285:113-116.
[97] Hayakawa K, Hardy RR, Stall AM, et al. Immunoglobulin-bearing B cells reconstitute and maintain the murine Ly-1 B cell lineage. European journal of immunology 1986;16:1313-1316.
[98] Wen L, Brill-Dashoff J, Shinton SA, et al. Evidence of marginal-zone B cell-positive selection in spleen. Immunity 2005;23:297-308.
[99] Martin F, Kearney JF. Positive selection from newly formed to marginal zone B cells depends on the rate of clonal production, CD19, and btk. Immunity 2000; 12:39-49.
[100] Godin I, Dieterlen-Lievre F, Cumano A. Emergence of multipotent hemopoietic cells in the yolk sac and paraaortic splanchnopleura in mouse embryos, beginning at 8.5 days postcoitus. Proceedings of the National Academy of Sciences of the United States of America 1995;92:773-777.
[101] Sugiyama D, Ogawa M, Nakao K, et al. B cell potential can be obtained from pre- circulatory yolk sac, but with low frequency. Developmental biology 2007;301.53-61.
[102] de Andres B, Gonzalo P, Minguet S, et al. The first 3 days of B-cell development in the mouse embryo. Blood 2002;100:4074-4081.
[103] Li YS, Hayakawa K, Hardy RR. The regulated expression of B lineage associated genes during B cell differentiation in bone marrow and fetal liver. The Journal of experimental medicine 1993; 178:951-960.
[104] Feeney AJ. Lack of N regions in fetal and neonatal mouse immunoglobulin V-D-J junctional sequences. The Journal of experimental medicine 1990; 172:1377-1390.
[105] Feeney AJ. Predominance of VH-D-JH junctions occurring at sites of short sequence homology results in limited junctional diversity in neonatal antibodies. J Immunol 1992; 149:222-229.
[106] Masmoudi H, Mota-Santos T, Huetz F, et al. All T15 Id-positive antibodies (but not the majority of VHT15+ antibodies) are produced by peritoneal CD5+ B lymphocytes. International immunology 1990;2:515-520.
[107] Briles DE, Forman C, Hudak S, et al. Anti-phosphorylcholine antibodies of the T15 idiotype are optimally protective against Streptococcus pneumoniae. The Journal of experimental medicine 1982;156:1177-1185.
[108] Benedict CL, Kearney JF. Increased junctional diversity in fetal B cells results in a loss of protective anti-phosphorylcholine antibodies in adult mice. Immunity 1999;10:607-617.
[109] Hardy RR. B-1 B cell development. J Immunol 2006; 177:2749-2754.
[110] Arnold LW, Pennell CA, McCray SK, et al. Development of B-1 cells: segregation of phosphatidyl choline-specific B cells to the B-1 population occurs after immunoglobulin gene expression. The Journal of experimental medicine 1994;179:1585-1595.
[111] Wasserman R, Li YS, Shinton SA, et al. A novel mechanism for B cell repertoire maturation based on response by B cell precursors to pre-B receptor assembly. The Journal of experimental medicine 1998;187:259-264.
[112] Hayakawa K, Asano M, Shinton SA, et al. Positive selection of anti-thy-1 autoreactive B-1 cells and natural serum autoantibody production independent from bone marrow B cell development. The Journal of experimental medicine 2003;197:87-99.
[113] Hayakawa K, Tarlinton D, Hardy RR. Absence of MHC class II expression distinguishes fetal from adult B lymphopoiesis in mice. J Immunol 1994; 152:4801- 4807.
[114] Lam KP, Stall AM. Major histocompatibility complex class II expression distinguishes two distinct B cell developmental pathways during ontogeny. The Journal of experimental medicine 1994;180:507-516.
[115] Tung JW, Mrazek MD, Yang Y, et al. Phenotypically distinct B cell development pathways map to the three B cell lineages in the mouse. Proceedings of the National Academy of Sciences of the United States of America 2006;103:6293-6298.
[116] Kantor AB, Merrill CE, Herzenberg LA, et al. An unbiased analysis of V(H)-D-J(H) sequences from B-1a, B-1b, and conventional B cells. J Immunol 1997;158:1175- 1186.
[117] Lalor PA, Herzenberg LA, Adams S, et al. Feedback regulation of murine Ly-1 B cell development. European journal of immunology 1989;19:507-513.
[118] Carvalho TL, Mota-Santos T, Cumano A, et al. Arrested B lymphopoiesis and persistence of activated B cells in adult interleukin 7(-/)- mice. The Journal of experimental medicine 2001;194:1141-1150.
[119] Miller JP, Izon D, DeMuth W, et al. The earliest step in B lineage differentiation from common lymphoid progenitors is critically dependent upon interleukin 7. The Journal of experimental medicine 2002; 196:705-711.
[120] von Freeden-Jeffry U, Vieira P, Lucian LA, et al. Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine. The Journal of experimental medicine 1995; 181:1519-1526.
[121] Dias S, Silva H, Jr., Cumano A, et al. Interleukin-7 is necessary to maintain the B cell potential in common lymphoid progenitors. The Journal of experimental medicine 2005 ;201:971-979.
[122] Vosshenrich CA, Cumano A, Muller W, et al. Pre-B cell receptor expression is necessary for thymic stromal lymphopoietin responsiveness in the bone marrow but not in the liver environment. Proceedings of the National Academy of Sciences of the United States of America 2004;101:11070-11075.
[123] Park LS, Martin U, Garka K, et al. Cloning of the murine thymic stromal lymphopoietin (TSLP) receptor: Formation of a functional heteromeric complex requires interleukin 7 receptor. The Journal of experimental medicine 2000; 192:659- 670.
[124] Ziegler SF, Liu YJ. Thymic stromal lymphopoietin in normal and pathogenic T cell development and function. Nature immunology 2006;7:709-714.
[125] Vosshenrich CA, Cumano A, Muller W, et al. Thymic stromal-derived lymphopoietin distinguishes fetal from adult B cell development. Nature immunology 2003;4:773- 779.
[126] Sitnicka E, Brakebusch C, Martensson IL, et al. Complementary signaling through flt3 and interleukin-7 receptor alpha is indispensable for fetal and adult B cell genesis. The Journal of experimental medicine 2003;198:1495-1506.
[127] Lyman SD, Jacobsen SE. c-kit ligand and Flt3 ligand: stem/progenitor cell factors with overlapping yet distinct activities. Blood 1998;91:1101-1134.
[128] McKenna HJ, Stocking KL, Miller RE, et al. Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic progenitor cells, dendritic cells, and natural killer cells. Blood 2000;95:3489-3497.
[129] Mackarehtschian K, Hardin JD, Moore KA, et al. Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors. Immunity 1995;3:147-161.
[130] Sitnicka E, Bryder D, Theilgaard-Monch K, et al. Key role of flt3 ligand in regulation of the common lymphoid progenitor but not in maintenance of the hematopoietic stem cell pool. Immunity 2002;17:463-472.
[131] Kikuchi K, Kondo M. Developmental switch of mouse hematopoietic stem cells from fetal to adult type occurs in bone marrow after birth. Proceedings of the National Academy of Sciences of the United States of America 2006; 103:17852-17857.
[132] Coulomb-L'Hermin A, Amara A, Schiff C, et al. Stromal cell-derived factor 1 (SDF-1) and antenatal human B cell lymphopoiesis: expression of SDF-1 by mesothelial cells and biliary ductal plate epithelial cells. Proceedings of the National Academy of Sciences of the United States of America 1999;96:8585-8590.
[133] Nagasawa T, Kikutani H, Kishimoto T. Molecular cloning and structure of a pre-B- cell growth-stimulating factor. Proceedings of the National Academy of Sciences of the United States of America 1994;91:2305-2309.
[134] Ma Q, Jones D, Springer TA. The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment. Immunity 1999; 10:463-471.
[135] Foussat A, Balabanian K, Amara A, et al. Production of stromal cell-derived factor 1 by mesothelial cells and effects of this chemokine on peritoneal B lymphocytes. European journal of immunology 2001;31:350-359.
[136] Ma Q, Jones D, Borghesani PR, et al. Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proceedings of the National Academy of Sciences of the United States of America 1998;95:9448-9453.
[137] Nagasawa T, Hirota S, Tachibana K, et al. Defects of B-cell lymphopoiesis and bone- marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 1996;382:635-638.
[138] Balabanian K, Lagane B, Infantino S, et al. The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. The Journal of biological chemistry 2005;280:35760-35766.
[139] Tominaga A, Takaki S, Koyama N, et al. Transgenic mice expressing a B cell growth and differentiation factor gene (interleukin 5) develop eosinophilia and autoantibody production. The Journal of experimental medicine 1991; 173:429-437.
[140] Kopf M, Brombacher F, Hodgkin PD, et al. IL-5-deficient mice have a developmental defect in CD5+ B-1 cells and lack eosinophilia but have normal antibody and cytotoxic T cell responses. Immunity 1996;4:15-24.
[141] Yoshida T, Ikuta K, Sugaya H, et al. Defective B-1 cell development and impaired immunity against Angiostrongylus cantonensis in IL-5R alpha-deficient mice. Immunity 1996;4:483-494.
[142] Hayakawa K, Hardy RR, Parks DR, et al. The "Ly-1 B" cell subpopulation in normal immunodefective, and autoimmune mice. The Journal of experimental medicine 1983;157:202-218.
[143] Wen L, Shinton SA, Hardy RR, et al. Association of B-1 B cells with follicular dendritic cells in spleen. J Immunol 2005;174:6918-6926.
[144] Ansel KM, Harris RB, Cyster JG. CXCL13 is required for B1 cell homing, natural antibody production, and body cavity immunity. Immunity 2002; 16:67-76.
[145] Hopken UE, Achtman AH, Kruger K, et al. Distinct and overlapping roles of CXCR5 and CCR7 in B-1 cell homing and early immunity against bacterial pathogens. J Leukoc Biol 2004;76:709-718.
[146] Ha SA, Tsuji M, Suzuki K, et al. Regulation of B1 cell migration by signals through Toll-like receptors. The Journal of experimental medicine 2006;203:2541-2550.
[147] Balabanian K, Foussat A, Bouchet-Delbos L, et al. Interleukin-10 modulates the sensitivity of peritoneal B lymphocytes to Chemokines with opposite effects on stromal cell-derived factor-1 and B-lymphocyte chemoattractant. Blood 2002;99:427- 436.
[148] Kuhn R, Lohler J, Rennick D, et al. Interleukin- 10-deficient mice develop chronic enterocolitis. Cell 1993;75:263-274.
[149] Murakami M, Tsubata T, Shinkura R, et al. Oral administration of lipopolysaccharides activates B-1 cells in the peritoneal cavity and lamina propria of the gut and induces autoimmune symptoms in an autoantibody transgenic mouse. The Journal of experimental medicine 1994; 180:111 -121.
[150] Macpherson AJ, Uhr T. Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science 2004;303:1662-1665.
[151] Fagarasan S, Shinkura R, Kamata T, et al. Alymphoplasia (aly)-type nuclear factor kappaB-inducing kinase (NIK) causes defects in secondary lymphoid tissue chemokine receptor signaling and homing of peritoneal cells to the gut-associated lymphatic tissue system. The Journal of experimental medicine 2000; 191:1477-1486.
[152] Mora JR, Iwata M, Eksteen B, et al. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 2006;314:1157-1160.
[153] Baumgarth N, Tung JW, Herzenberg LA. Inherent specificities in natural antibodies: a key to immune defense against pathogen invasion. Springer seminars in immunopathology 2005;26:347-362.
[154] Tumang JR, Frances R, Yeo SG, et al. Spontaneously Ig-secreting B-1 cells violate the accepted paradigm for expression of differentiation-associated transcription factors. J Immunol 2005;174:3173-3177.
[155] Savitsky D, Calame K. B-1 B lymphocytes require Blimp-1 for immunoglobulin secretion. The Journal of experimental medicine 2006;203:2305-2314.
[156] Briles DE, Claflin JL, Schroer K, et al. Mouse Igg3 antibodies are highly protective against infection with Streptococcus pneumoniae. Nature 1981;294:88-90.
[157] Briles DE, Nahm M, Schroer K, et al. Antiphosphocholine antibodies found in normal mouse serum are protective against intravenous infection with type 3 streptococcus pneumoniae. The Journal of experimental medicine 1981;153:694-705.
[158] Ochsenbein AF, Fehr T, Lutz C, et al. Control of early viral and bacterial distribution and disease by natural antibodies. Science 1999;286:2156-2159.
[159] Baumgarth N, Chen J, Herman OC, et al. The role of B-1 and B-2 cells in immune protection from influenza virus infection. Current topics in microbiology and immunology 2000;252:163-169.
[160] Baumgarth N, Herman OC, Jager GC, et al. Innate and acquired humoral immunities to influenza virus are mediated by distinct arms of the immune system. Proceedings of the National Academy of Sciences of the United States of America 1999;96:2250- 2255.
[161] Boes M, Prodeus AP, Schmidt T, et al. A critical role of natural immunoglobulin M in immediate defense against systemic bacterial infection. The Journal of experimental medicine 1998;188:2381-2386.
[162] Reid RR, Prodeus AP, Khan W, et al. Endotoxin shock in antibody-deficient mice: unraveling the role of natural antibody and complement in the clearance of lipopolysaccharide. J Immunol 1997; 159:970-975.
[163] Shaw PX, Goodyear CS, Chang MK, et al. The autoreactivity of anti- phosphorylcholine antibodies for atherosclerosis-associated neo-antigens and apoptotic cells. J Immunol 2003;170:6151-6157.
[164] Binder CJ, Silverman GJ. Natural antibodies and the autoimmunity of atherosclerosis. Springer seminars in immunopathology 2005;26:385-404.
[165] Murakami M, Yoshioka H, Shirai T, et al. Prevention of autoimmune symptoms in autoimmune-prone mice by elimination of B-1 cells. International immunology 1995;7:877-882.
[166] Steinberg BJ, Smathers PA, Frederiksen K, et al. Ability of the xid gene to prevent autoimmunity in (NZB X NZW)F1 mice during the course of their natural history, after polyclonal stimulation, or following immunization with DNA. The Journal of clinical investigation 1982;70:587-597.
[167] Kroese FG, Butcher EC, Stall AM, et al. Many of the IgA producing plasma cells in murine gut are derived from self-replenishing precursors in the peritoneal cavity. International immunology 1989;l:75-84.
[168] Kroese FG, Butcher EC, Stall AM, et al. A major peritoneal reservoir of precursors for intestinal IgA plasma cells. Immunol Invest 1989; 18:47-58.
[169] Macpherson AJ, Gatto D, Sainsbury E, et al. A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. Science 2000;288:2222-2226.
[170] Snider DP, Liang H, Switzer I, et al. IgA production in MHC class H-deficient mice is primarily a function of B-1a cells. International immunology 1999;11:191-198.
[171] Bergqvist P, Gardby E, Stensson A, et al. Gut IgA class switch recombination in the absence of CD40 does not occur in the lamina propria and is independent of germinal centers. J Immunol 2006; 177:7772-7783.
[172] de Waard R, Dammers PM, Tung JW, et al. Presence of germline and full-length IgA RNA transcripts among peritoneal B-1 cells. Developmental immunology 1998;6:81- 87.
[173] Binder CJ, Horkko S, Dewan A, et al. Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL. Nature medicine 2003;9:736-743.
[174] Martin F, Oliver AM, Kearney JF. Marginal zone and B1 B cells unite in the early response against T-independent blood-borne particulate antigens. Immunity 2001;14:617-629.
[175] Forster I, Rajewsky K. Expansion and functional activity of Ly-1+ B cells upon transfer of peritoneal cells into allotype-congenic, newborn mice. European journal of immunology 1987; 17:521-528.
[176] Hayakawa K, Hardy RR, Honda M, et al. Ly-1 B cells: functionally distinct lymphocytes that secrete IgM autoantibodies. Proceedings of the National Academy of Sciences of the United States of America 1984;81.2494-2498.
[177] Lopes-Carvalho T, Kearney JF. Development and selection of marginal zone B cells. Immunological reviews 2004;197:192-205.
[178] Hsu MC, Toellner KM, Vinuesa CG, et al. B cell clones that sustain long-term plasmablast growth in T-independent extrafollicular antibody responses. Proceedings of the National Academy of Sciences of the United States of America 2006; 103:5905- 5910.
[179] Haas KM, Poe JC, Steeber DA, et al. B-1a and B-1b cells exhibit distinct developmental requirements and have unique functional roles in innate and adaptive immunity to S. pneumoniae. Immunity 2005;23:7-18.
[180] Alugupalli KR, Gerstein RM, Chen J, et al. The resolution of relapsing fever borreliosis requires IgM and is concurrent with expansion of B1b lymphocytes. J Immunol 2003;170:3819-3827.
[181] Alugupalli KR, Leong JM, Woodland RT, et al. B1b lymphocytes confer T cell- independent long-lasting immunity. Immunity 2004;21:379-390.
[182] Balazs M, Martin F, Zhou T, et al. Blood dendritic cells interact with splenic marginal zone B cells to initiate T-independent immune responses. Immunity 2002;17:341-352.
[183] Chelvarajan RL, Raithatha R, Venkataraman C, et al. CpG oligodeoxynucleotides overcome the unresponsiveness of neonatal B cells to stimulation with the thymus- independent stimuli anti-IgM and TNP-Ficoll. European journal of immunology 1999;29:2808-2818.
[184]Lenert P,Brummel R,Field EH,et al.TLR-9 activation of marginal zone B cells in lupus mice regulates immunity through increased IL-10 production.Journal of clinical immunology 2005;25:29-40.
[185]Burke F,Stagg AJ,Bedford PA,et al.IL-10-producing B220+CD11c- APC in mouse spleen.J Immunol 2004;173:2362-2372.
[186]O'Garra A,Chang R,Go N,et al.Ly-1 B(B-1) cells are the main source of B cell-derived interleukin 10.European journal of immunology 1992;22:711-717.
[187]Fillatreau S,Sweenie CH,McGeachy MJ,et al.B cells regulate autoimmunity by provision of IL-10.Nature immunology 2002;3:944-950.
[188]Mauri C,Gray D,Mushtaq N,et al.Prevention of arthritis by interleukin 10-producing B cells.The Journal of experimental medicine 2003;197:489-501.
[189]Mangan NE,Fallon RE,Smith P,et al.Helminth infection protects mice from anaphylaxis via IL-10-producing B cells.J Immunol 2004;173:6346-6356.
[190]Ishida H,Hastings R,Kearney J,et al.Continuous anti-interleukin 10 antibody administration depletes mice of Ly-1 B cells but not conventional B cells.The Journal of experimental medicine 1992;175:1213-1220.
[191]Peng B,Mehta NH,Femandes H,et al.Growth inhibition of malignant CD5+B(B-1)cells by antisense IL-10 oligonucleotide.Leukemia research 1995;19:159-167.
[192]Harris DP,Haynes L,Sayles PC,et al.Reciprocal regulation of polarized cytokine production by effector B and T cells.Nature immunology 2000;1:475-482.
[193]Harris DP,Goodrich S,Mohrs K,et al.Cutting edge:the development of IL-4-producing B cells(B effector 2 cells) is controlled by IL-4,IL-4 receptor alpha,and Th2 cells.J Immunol 2005;175:7103-7107.
[194]Harris DP,Goodrich S,Gerth AJ,et al.Regulation of IFN-gamma production by B effector 1 cells:essential roles for T-bet and the IFN-gamma receptor.J Immunol 2005;174:6781-6790.
[195]Akira S,Uematsu S,Takeuchi O.Pathogen recognition and innate immunity.Cell 2006;124:783-801.
[196]Akira S,Takeda K.Toll-like receptor signalling.Nature reviews 2004;4:499-511.
[197]Takaoka A,Yanai H,Kondo S,et al.Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors.Nature 2005;434:243-249.
[198]Hacker H,Redecke V,Blagoev B,et al.Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6.Nature 2006;439:204-207.
[199]Oganesyan G,Saha SK,Guo B,et al.Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response.Nature 2006;439:208-211.
[200]Kawai T,Sato S,Ishii KJ,et al.Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6.Nature immunology 2004;5:1061-1068.
[201]Uematsu S,Sato S,Yamamoto M,et al.Interleukin-1 receptor-associated kinase-1plays an essential role for Toll-like receptor(TLR)7- and TLR9-mediated interferon-{alpha}induction.The Journal of experimental medicine 2005;201:915-923.
[202]Kawai T,Adachi O,Ogawa T,et al.Unresponsiveness of MyD88-deficient mice to endotoxin.Immunity 1999;11:115-122.
[203]Kato H,Takeuchi O,Sato S,et al.Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses.Nature 2006;441:101-105.
[204]Hornung V,Ellegast J,Kim S,et al.5'-Triphosphate RNA is the ligand for RIG-I.Science 2006;314:994-997.
[205]Pichlmair A,Schulz O,Tan CP,et al.RIG-I-mediated antiviral responses to single-stranded RNA bearing 5'-phosphates.Science 2006;314:997-1001.
[206] Saito T, Hirai R, Loo YM, et al. Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2. Proceedings of the National Academy of Sciences of the United States of America 2007; 104:582-587.
[207] Fritz JH, Ferrero RL, Philpott DJ, et al. Nod-like proteins in immunity, inflammation and disease. Nature immunology 2006;7:1250-1257.
[208] Hsu YM, Zhang Y, You Y, et al. The adaptor protein CARD9 is required for innate immune responses to intracellular pathogens. Nature immunology 2007;8:198-205.
[209] Miao EA, Alpuche-Aranda CM, Dors M, et al. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf. Nature immunology 2006;7:569- 575.
[210] Franchi L, Amer A, Body-Malapel M, et al. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin lbeta in salmonella-infected macrophages. Nature immunology 2006;7:576-582.
[211] Molofsky AB, Byrne BG, Whitfield NN, et al. Cytosolic recognition of flagellin by mouse macrophages restricts Legionella pneumophila infection. The Journal of experimental medicine 2006;203:1093-1104.
[212] Robinson MJ, Sancho D, Slack EC, et al. Myeloid C-type lectins in innate immunity. Nature immunology 2006;7:1258-1265.
[213] Brown GD, Gordon S. Immune recognition. A new receptor for beta-glucans. Nature 2001;413:36-37.
[214] Gantner BN, Simmons RM, Canavera SJ, et al. Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor 2. The Journal of experimental medicine 2003; 197:1107-1117.
[215] Rogers NC, Slack EC, Edwards AD, et al. Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity 2005;22:507-517.
[216] Gross O, Gewies A, Finger K, et al. Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity. Nature 2006;442:651-656.
[217] Taylor PR, Tsoni SV, Willment JA, et al. Dectin-1 is required for beta-glucan recognition and control of fungal infection. Nature immunology 2007;8:31-38.
[218] Saijo S, Fujikado N, Furuta T, et al. Dectin-1 is required for host defense against Pneumocystis carinii but not against Candida albicans. Nature immunology 2007;8:39-46.
[219] Mansell A, Smith R, Doyle SL, et al. Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation. Nature immunology 2006;7:148-155.
[220] Fenner JE, Starr R, Cornish AL, et al. Suppressor of cytokine signaling 1 regulates the immune response to infection by a unique inhibition of type I interferon activity. Nature immunology 2006;7:33-39.
[221] An H, Zhao W, Hou J, et al. SHP-2 Phosphatase Negatively Regulates the TRIF Adaptor Protein-Dependent Type I Interferon and Proinflammatory Cytokine Production. Immunity 2006;25:919-928.
[222] Divanovic S, Trompette A, Atabani SF, et al. Negative regulation of Toll-like receptor 4 signaling by the Toll-like receptor homolog RP105. Nature immunology 2005;6:571-578.
[223] Wald D, Qin J, Zhao Z, et al. SIGIRR, a negative regulator of Toll-like receptor- interleukin 1 receptor signaling. Nature immunology 2003;4:920-927.
[224] Brint EK, Xu D, Liu H, et al. ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance. Nature immunology 2004;5:373-379.
[225] Burns K, Janssens S, Brissoni B, et al. Inhibition of interleukin 1 receptor/Toll-like receptor signaling through the alternatively spliced, short form of MyD88 is due to its failure to recruit IRAK-4. The Journal of experimental medicine 2003;197:263-268.
[226] Kobayashi K, Hernandez LD, Galan JE, et al. IRAK-M is a negative regulator of Toll- like receptor signaling. Cell 2002;110:191-202.
[227] Isaacs A, Lindenmann J. Virus interference. I. The interferon. Proceedings of the Royal Society of London Series B, Containing papers of a Biological character 1957;147:258-267.
[228] Theofilopoulos AN, Baccala R, Beutler B, et al. Type I interferons (alpha/beta) in immunity and autoimmunity. Annual review of immunology 2005;23:307-336.
[229] Ank N, West H, Paludan SR. IFN-lambda: novel antiviral cytokines. J Interferon Cytokine Res 2006;26:373-379.
[230] Honda K, Yanai H, Negishi H, et al. IRF-7 is the master regulator of type-I interferon- dependent immune responses. Nature 2005;434:772-777.
[231] Lee HK, Lund JM, Ramanathan B, et al. Autophagy-dependent viral recognition by plasmacytoid dendritic cells. Science 2007;315:1398-1401.
[232] Duramad O, Fearon KL, Chan JH, et al. IL-10 regulates plasmacytoid dendritic cell response to CpG-containing immunostimulatory sequences. Blood 2003;102:4487- 4492.
[233] Boonstra A, Rajsbaum R, Holman M, et al. Macrophages and myeloid dendritic cells, but not plasmacytoid dendritic cells, produce IL-10 in response to MyD88- and TRIF- dependent TLR signals, and TLR-independent signals. J Immunol 2006; 177:7551- 7558.
[234] Bave U, Vallin H, Alm GV, et al. Activation of natural interferon-alpha producing cells by apoptotic U937 cells combined with lupus IgG and its regulation by cytokines. Journal of autoimmunity 2001; 17:71-80.
[235] Palucka AK, Blanck JP, Bennett L, et al. Cross-regulation of TNF and IFN-alpha in autoimmune diseases. Proceedings of the National Academy of Sciences of the United States of America 2005;102:3372-3377.
[236] Bjorck P. Dendritic cells exposed to herpes simplex virus in vivo do not produce IFN- alpha after rechallenge with virus in vitro and exhibit decreased T cell alloreactivity. J Immunol 2004; 172:5396-5404.
[237] Kerkmann M, Costa LT, Richter C, et al. Spontaneous formation of nucleic acid-based nanoparticles is responsible for high interferon-alpha induction by CpG-A in plasmacytoid dendritic cells. The Journal of biological chemistry 2005;280:8086- 8093.
[238] Krieg AM. CpG motifs in bacterial DNA and their immune effects. Annual review of immunology 2002;20:709-760.
[239] Hartmann G, Battiany J, Poeck H, et al. Rational design of new CpG oligonucleotides that combine B cell activation with high IFN-alpha induction in plasmacytoid dendritic cells. European journal of immunology 2003;33:1633-1641.
[240] Marshall JD, Fearon K, Abbate C, et al. Identification of a novel CpG DNA class and motif that optimally stimulate B cell and plasmacytoid dendritic cell functions. Journal of leukocyte biology 2003 ;73:781-792.
[241] Honda K, Ohba Y, Yanai H, et al. Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Nature 2005;434:1035-1040.
[242] Guiducci C, Ott G, Chan JH, et al. Properties regulating the nature of the plasmacytoid dendritic cell response to Toll-like receptor 9 activation. The Journal of experimental medicine 2006.
[243] Mohty M, Vialle-Castellano A, Nunes JA, et al. IFN-alpha skews monocyte differentiation into Toll-like receptor 7-expressing dendritic cells with potent functional activities. J Immunol 2003;171:3385-3393.
[244] Gray RC, Kuchtey J, Harding CV. CpG-B ODNs potently induce low levels of IFN- {alpha} {beta} and induce IFN-{alpha} {beta}-dependent MHC-I cross-presentation in DCs as effectively as CpG-A and CpG-C ODNs. Journal of leukocyte biology 2007.
[245] Ishii KJ, Coban C, Kato H, et al. A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA. Nature immunology 2006;7.40-48.
[246] Stetson DB, Medzhitov R. Recognition of Cytosolic DNA activates an IRF3-dependent innate immune response. Immunity 2006;24:93-103.
[247] Honda K, Takaoka A, Taniguchi T. Type I interferon [corrected] gene induction by the interferon regulatory factor family of transcription factors. Immunity 2006;25:349- 360.
[248] van Boxel-Dezaire AH, Rani MR, Stark GR. Complex modulation of cell type- specific signaling in response to type I interferons. Immunity 2006;25:361-372.
[249] Stark GR, Kerr IM, Williams BR, et al. How cells respond to interferons. Annual review of biochemistry 1998;67:227-264.
[250] Pien GC, Nguyen KB, Malmgaard L, et al. A unique mechanism for innate cytokine promotion of T cell responses to viral infections. J Immunol 2002; 169:5827-5837.
[251] Nguyen KB, Cousens LP, Doughty LA, et al. Interferon alpha/beta-mediated inhibition and promotion of interferon gamma: STAT1 resolves a paradox. Nature immunology 2000; 1:70-76.
[252] Nguyen KB, Watford WT, Salomon R, et al. Critical role for STAT4 activation by type 1 interferons in the interferon-gamma response to viral infection. Science 2002;297:2063-2066.
[253] Bromberg JF, Horvath CM, Wen Z, et al. Transcriptionally active Statl is required for the antiproliferative effects of both interferon alpha and interferon gamma. Proceedings of the National Academy of Sciences of the United States of America 1996;93:7673-7678.
[254] Tanabe Y, Nishibori T, Su L, et al. Cutting edge: role of STAT1, STAT3, and STAT5 in IFN-alpha beta responses in T lymphocytes. J Immunol 2005;174:609-613.
[255] Wong LH, Sim H, Chatterjee-Kishore M, et al. Isolation and characterization of a human STAT1 gene regulatory element. Inducibility by interferon (IFN) types I and II and role of IFN regulatory factor-1. The Journal of biological chemistry 2002;277:19408-19417.
[256] Marrack P, Kappler J, Mitchell T. Type I interferons keep activated T cells alive. The Journal of experimental medicine 1999;189:521-530.
[257] Tough DF, Sun S, Sprent J. T cell stimulation in vivo by lipopolysaccharide (LPS). The Journal of experimental medicine 1997;185:2089-2094.
[258] Tough DF, Borrow P, Sprent J. Induction of bystander T cell proliferation by viruses and type I interferon in vivo. Science 1996;272:1947-1950.
[259] Curtsinger JM, Valenzuela JO, Agarwal P, et al. Type I IFNs provide a third signal to CD8 T cells to stimulate clonal expansion and differentiation. J Immunol 2005;174:4465-4469.
[260] Kolumam GA, Thomas S, Thompson LJ, et al. Type I interferons act directly on CD8 T cells to allow clonal expansion and memory formation in response to viral infection. The Journal of experimental medicine 2005;202:637-650.
[261] Hervas-Stubbs S, Rueda P, Lopez L, et al. Insect baculoviruses strongly potentiate adaptive immune responses by inducing type I IFN. J Immunol 2007;178:2361-2369.
[262] Le Bon A, Durand V, Kamphuis E, et al. Direct stimulation of T cells by type I IFN enhances the CD8+ T cell response during cross-priming. J Immunol 2006; 176:4682- 4689.
[263] Gil MP, Salomon R, Louten J, et al. Modulation of STAT1 protein levels: a mechanism shaping CD8 T-cell responses in vivo. Blood 2006; 107:987-993.
[264] Zhang X, Sun S, Hwang I, et al. Potent and selective stimulation of memory- phenotype CD8+ T cells in vivo by IL-15. Immunity 1998;8:591-599.
[265] Orange JS, Biron CA. Characterization of early IL-12, IFN-alphabeta, and TNF effects on antiviral state and NK cell responses during murine cytomegalovirus infection. J Immunol 1996; 156:4746-4756.
[266] Andoniou CE, van Dommelen SL, Voigt V, et al. Interaction between conventional dendritic cells and natural killer cells is integral to the activation of effective antiviral immunity. Nature immunology 2005;6:1011-1019.
[267] Nguyen KB, Salazar-Mather TP, Dalod MY, et al. Coordinated and distinct roles for IFN-alpha beta, IL-12, and IL-15 regulation of NK cell responses to viral infection. J Immunol 2002; 169:4279-4287.
[268] Braun D, Caramalho I, Demengeot J. IFN-alpha/beta enhances BCR-dependent B cell responses. International immunology 2002;14:411-419.
[269] Jego G, Palucka AK, Blanck JP, et al. Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6. Immunity 2003;19:225-234.
[270] Le Bon A, Thompson C, Kamphuis E, et al. Cutting edge: enhancement of antibody responses through direct stimulation of B and T cells by type I IFN. J Immunol 2006; 176:2074-2078.
[271] Litinskiy MB, Nardelli B, Hilbert DM, et al. DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL. Nature immunology 2002;3:822-829.
[272] Wang J, Lin Q, Langston H, et al. Resident bone marrow macrophages produce type 1 interferons that can selectively inhibit interleukin-7-driven growth of B lineage cells. Immunity 1995;3:475-484.
[273] Lin Q, Dong C, Cooper MD. Impairment of T and B cell development by treatment with a type I interferon. The Journal of experimental medicine 1998;187:79-87.
[274] Muller U, Steinhoff U, Reis LF, et al. Functional role of type I and type II interferons in antiviral defense. Science 1994;264:1918-1921.
[275] Binder D, Fehr J, Hengartner H, et al. Virus-induced transient bone marrow aplasia: major role of interferon-alphafteta during acute infection with the noncytopathic lymphocytic choriomeningitis virus. The Journal of experimental medicine 1997;185:517-530.
[276] Kadowaki N, Antonenko S, Lau JY, et al. Natural interferon alpha/beta-producing cells link innate and adaptive immunity. The Journal of experimental medicine 2000;192:219-226.
[277] Dalod M, Salazar-Mather TP, Malmgaard L, et al. Interferon alpha/beta and interleukin 12 responses to viral infections: pathways regulating dendritic cell cytokine expression in vivo. The Journal of experimental medicine 2002;195:517-528.
[278] Shinohara ML, Lu L, Bu J, et al. Osteopontin expression is essential for interferon- alpha production by plasmacytoid dendritic cells. Nature immunology 2006;7:498- 506.
[279] Asselin-Paturel C, Brizard G, Chemin K, et al. Type I interferon dependence of plasmacytoid dendritic cell activation and migration. The Journal of experimental medicine 2005;201:1157-1167.
[280] Honda K, Sakaguchi S, Nakajima C, et al. Selective contribution of IFN-alpha/beta signaling to the maturation of dendritic cells induced by double-stranded RNA or viral infection. Proceedings of the National Academy of Sciences of the United States of America 2003;100:10872-10877.
[281] Montoya M, Schiavoni G, Mattei F, et al. Type I interferons produced by dendritic cells promote their phenotypic and functional activation. Blood 2002;99:3263-3271.
[282] Kuchtey J, Chefalo PJ, Gray RC, et al. Enhancement of dendritic cell antigen cross- presentation by CpG DNA involves type I IFN and stabilization of class I MHC mRNA. J Immunol 2005; 175:2244-2251.
[283] Le Bon A, Etchart N, Rossmann C, et al. Cross-priming of CD8+ T cells stimulated by virus-induced type I interferon. Nature immunology 2003;4:1009-1015.
[284] Le Bon A, Schiavoni G, D'Agostino G, et al. Type i interferons potently enhance humoral immunity and can promote isotype switching by stimulating dendritic cells in vivo. Immunity 2001; 14:461-470.
[285] Gautier G, Humbert M, Deauvieau F, et al. A type I interferon autocrine-paracrine loop is involved in Toll-like receptor-induced interleukin-12p70 secretion by dendritic cells. The Journal of experimental medicine 2005;201:1435-1446.
[286] Pollara G, Handley ME, Kwan A, et al. Autocrine type I interferon amplifies dendritic cell responses to lipopolysaccharide via the nuclear factor-kappaB/p38 pathways. Scandinavian journal of immunology 2006;63:151 -154.
[287] Flores RR, Diggs KA, Tait LM, et al. IFN-gamma negatively regulates CpG-induced IL-10 in bone marrow-derived dendritic cells. J Immunol 2007;178:211-218.
[288] Heystek HC, den Drijver B, Kapsenberg ML, et al. Type I IFNs differentially modulate IL-12p70 production by human dendritic cells depending on the maturation status of the cells and counteract IFN-gamma-mediated signaling. Clinical immunology (Orlando, Fla 2003;107:170-177.
[289] Luft T, Luetjens P, Hochrein H, et al. IFN-alpha enhances CD40 ligand-mediated activation of immature monocyte-derived dendritic cells. International immunology 2002;14:367-380.
[290] McRae BL, Semnani RT, Hayes MP, et al. Type I IFNs inhibit human dendritic cell IL-12 production and Th1 cell development. J Immunol 1998; 160:4298-4304.
[291] Cousens LP, Orange JS, Su HC, et al. Interferon-alpha/beta inhibition of interleukin 12 and interferon-gamma production in vitro and endogenously during viral infection. Proceedings of the National Academy of Sciences of the United States of America 1997;94:634-639.
[292] Krug A, French AR, Barchet W, et al. TLR9-dependent recognition of MCMV by IPC and DC generates coordinated cytokine responses that activate antiviral NK cell function. Immunity 2004;21:107-119.
[293] Longman RS, Braun D, Pellegrini S, et al. Dendritic-cell maturation alters intracellular signaling networks, enabling differential effects of IFN-{alpha}/{beta} on antigen cross-presentation. Blood 2007; 109:1113-1122.
[294] Taniguchi T, Takaoka A. The interferon-alpha/beta system in antiviral responses: a multimodal machinery of gene regulation by the IRF family of transcription factors. Current opinion in immunology 2002;14:l 11-116.
[295] Tassiulas I, Hu X, Ho H, et al. Amplification of IFN-alpha-induced STAT1 activationand inflammatory function by Syk and ITAM-containing adaptors. Nature immunology 2004;5:l 181-1189.
[296] Byrnes AA, Ma X, Cuomo P, et al. Type I interferons and IL-12: convergence and cross-regulation among mediators of cellular immunity. European journal of immunology 2001 ;31:2026-2034.
[297] Sharif MN, Sosic D, Rothlin CV, et al. Twist mediates suppression of inflammation by type I IFNs and Axl. The Journal of experimental medicine 2006;203:1891-1901.
[298] Sauer I, Schaljo B, Vogl C, et al. Interferons limit inflammatory responses by induction of tristetraprolin. Blood 2006; 107:4790-4797.
[299] Ho HH, Ivashkiv LB. Role of STAT3 in type I interferon responses. Negative regulation of STAT1-dependent inflammatory gene activation. The Journal of biological chemistry 2006;281:14111-14118.
[300] Karaghiosoff M, Steinborn R, Kovarik P, et al. Central role for type I interferons and Tyk2 in lipopolysaccharide-induced endotoxin shock. Nature immunology 2003;4:471-477.
[301] Weighardt H, Kaiser-Moore S, Schlautkotter S, et al. Type I IFN modulates host defense and late hyperinflammation in septic peritonitis. J Immunol 2006;177:5623- 5630.
[302] Mahieu T, Park JM, Revets H, et al. The wild-derived inbred mouse strain SPRET/Ei is resistant to LPS and defective in IFN-beta production. Proceedings of the National Academy of Sciences of the United States of America 2006;103:2292-2297.
[303] Ronnblom L, Eloranta ML, Alm GV. The type I interferon system in systemic lupus erythematosus. Arthritis Rheum 2006;54:408-420.
[304] Banchereau J, Pascual V. Type I interferon in systemic lupus erythematosus and other autoimmune diseases. Immunity 2006;25:383-392.
[305] Decker T, Muller M, Stockinger S. The yin and yang of type I interferon activity in bacterial infection. Nature reviews 2005;5:675-687.
[306] Koga R, Hamano S, Kuwata H, et al. TLR-Dependent Induction of IFN-beta Mediates Host Defense against Trypanosoma cruzi. J Immunol 2006; 177:7059-7066.
[307] Zamvil SS, Steinman L. Diverse targets for intervention during inflammatory and neurodegenerative phases of multiple sclerosis. Neuron 2003;38:685-688.
[308] Teige I, Liu Y, Issazadeh-Navikas S. IFN-beta inhibits T cell activation capacity of central nervous system APCs. J Immunol 2006; 177:3542-3553.
[309] Tuohy VK, Yu M, Yin L, et al. Modulation of the IL-10/IL-12 cytokine circuit by interferon-beta inhibits the development of epitope spreading and disease progression in murine autoimmune encephalomyelitis. J Neuroimmunol 2000; 111:55-63.
[310] Floris S, Ruuls SR, Wierinckx A, et al. Interferon-beta directly influences monocyte infiltration into the central nervous system. J Neuroimmunol 2002; 127:69-79.
[311] Katakura K, Lee J, Rachmilewitz D, et al. Toll-like receptor 9-induced type I IFN protects mice from experimental colitis. The Journal of clinical investigation 2005 ;115:695-702.
[312] Geissmann F, Jung S, Littman DR. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 2003;19:71-82.
[313] Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nature reviews 2005;5:953-964.
[314] Bennouna S, Denkers EY. Microbial antigen triggers rapid mobilization of TNF-alpha to the surface of mouse neutrophils transforming them into inducers of high-level dendritic cell TNF-alpha production. J Immunol 2005; 174:4845-4851.
[315] Bliss SK, Butcher BA, Denkers EY. Rapid recruitment of neutrophils containing prestored IL-12 during microbial infection. J Immunol 2000; 165:4515-4521.
[316] Romani L, Mencacci A, Cenci E, et al. Neutrophil production of IL-12 and IL-10 in candidiasis and efficacy of IL-12 therapy in neutropenic mice. J Immunol 1997;158:5349-5356.
[317] Yi AK, Yoon JG, Yeo SJ, et al. Role of mitogen-activated protein kinases in CpG DNA-mediated IL-10 and IL-12 production: central role of extracellular signal- regulated kinase in the negative feedback loop of the CpG DNA-mediated Th1 response. J Immunol 2002;168:4711-4720.
[318] Lucas M, Zhang X, Prasanna V, et al. ERK activation following macrophage FcgammaR ligation leads to chromatin modifications at the IL-10 locus. J Immunol 2005; 175:469-477.
[319] Bliss SK, Zhang Y, Denkers EY. Murine neutrophil stimulation by Toxoplasma gondii antigen drives high level production of IFN-gamma-independent IL-12. J Immunol 1999;163:2081-2088.
[320] Chelvarajan RL, Collins SM, Doubinskaia IE, et al. Defective macrophage function in neonates and its impact on unresponsiveness of neonates to polysaccharide antigens. Journal of leukocyte biology 2004;75:982-994.
[321] Moore KW, de Waal Malefyt R, Coffman RL, et al. Interleukin-10 and the interleukin- 10 receptor. Annual review of immunology 2001;19:683-765.
[322] Mizoguchi A, Bhan AK. A case for regulatory B cells. J Immunol 2006; 176:705-710.
[323] Brightbill HD, Plevy SE, Modlin RL, et al. A prominent role for Sp1 during lipopolysaccharide-mediated induction of the IL-10 promoter in macrophages. J Immunol 2000; 164:1940-1951.
[324] Cao S, Liu J, Song L, et al. The protooncogene c-Maf is an essential transcription factor for IL-10 gene expression in macrophages. J Immunol 2005;174:3484-3492.
[325] Benkhart EM, Siedlar M, Wedel A, et al. Role of Stat3 in lipopolysaccharide-induced IL-10 gene expression. J Immunol 2000; 165:1612-1617.
[326] Cao S, Zhang X, Edwards JP, et al. NF-kappaB1 (p50) homodimers differentially regulate pro- and anti-inflammatory cytokines in macrophages. The Journal of biological chemistry 2006;281:26041-26050.
[327] Qian C, Jiang X, An H, et al. TLR agonists promote ERK-mediated preferential IL-10 production of regulatory dendritic cells (diffDCs), leading to NK-cell activation. Blood 2006;108:2307-2315.
[328] Yang Z, Mosser DM, Zhang X. Activation of the MAPK, ERK, following Leishmania amazonensis infection of macrophages. J Immunol 2007;178:1077-1085.
[329] Zhang X, Edwards JP, Mosser DM. Dynamic and transient remodeling of the macrophage IL-10 promoter during transcription. J Immunol 2006; 177:1282-1288.
[330] Teige I, Treschow A, Teige A, et al. IFN-beta gene deletion leads to augmented and chronic demyelinating experimental autoimmune encephalomyelitis. J Immunol 2003;170:4776-4784.
[331] Yarilina A, Dicarlo E, Ivashkiv LB. Suppression of the Effector Phase of Inflammatory Arthritis by Double-Stranded RNA Is Mediated by Type I IFNs. J Immunol 2007; 178:2204-2211.
[332] Bengtsson AA, Sturfelt G, Truedsson L, et al. Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not with antiretroviral antibodies. Lupus 2000;9:664-671.
[333] Bennett L, Palucka AK, Arce E, et al. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. The Journal of experimental medicine 2003;197:711-723.
[334] Santiago-Raber ML, Baccala R, Haraldsson KM, et al. Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice. The Journal of experimental medicine 2003; 197:777-788.
[335] Braun D, Geraldes P, Demengeot J. Type I Interferon controls the onset and severity of autoimmune manifestations in lpr mice. Journal of autoimmunity 2003;20:15-25.
[336] Jorgensen TN, Thurman J, Izui S, et al. Genetic susceptibility to PolyI:C-induced IFNalpha/beta-dependent accelerated disease in lupus-prone mice. Genes Immun 2006;7:555-567.
[337] Magnusson M, Zare F, Tarkowski A. Requirement of type I interferon signaling for arthritis triggered by double-stranded RNA. Arthritis and rheumatism 2006;54:148- 157.
[338] Vallin H, Perers A, Alm GV, et al. Anti-double-stranded DNA antibodies and immunostimulatory plasmid DNA in combination mimic the endogenous IFN-alpha inducer in systemic lupus erythematosus. J Immunol 1999; 163:6306-6313.
[339] Mancuso G, Midiri A, Biondo C, et al. Type I IFN Signaling Is Crucial for Host Resistance against Different Species of Pathogenic Bacteria. J Immunol 2007;178:3126-3133.
[1] Tsolis RM, Kingsley RA, Townsend SM, et al. Of mice, calves, and men. Comparison of the mouse typhoid model with other Salmonella infections. Advances in experimental medicine and biology 1999;473:261-274.
[2] Stocker BA. Aromatic-dependent salmonella as anti-bacterial vaccines and as presenters of heterologous antigens or of DNA encoding them. Journal of biotechnology 2000;83:45-50.
[3] Sirard JC, Niedergang F, Kraehenbuhl JP. Live attenuated Salmonella: a paradigm of mucosal vaccines. Immunological reviews 1999;171:5-26.
[4] Schoen C, Stritzker J, Goebel W, et al. Bacteria as DNA vaccine carriers for genetic immunization. Int J Med Microbiol 2004;294:319-335.
[5] Hess J, Gentschev I, Miko D, et al. Superior efficacy of secreted over somatic antigen display in recombinant Salmonella vaccine induced protection against listeriosis. Proceedings of the National Academy of Sciences of the United States of America 1996;93:1458-1463.
[6] Hess J, Dietrich G, Gentschev I, et al. Protection against murine listeriosis by an attenuated recombinant Salmonella typhimurium vaccine strain that secretes the naturally somatic antigen superoxide dismutase. Infection and immunity 1997;65:1286-1292.
[7] Grillot-Courvalin C, Goussard S, Courvalin P. Wild-type intracellular bacteria deliver DNA into mammalian cells. Cellular microbiology 2002;4:177-186.
[8] Garmory HS, Titball RW, Brown KA, et al. Construction and evaluation of a eukaryotic expression plasmid for stable delivery using attenuated Salmonella. Microbial pathogenesis 2003;34:115-119.
[9] Brumell JH, Grinstein S. Salmonella redirects phagosomal maturation. Current opinion in microbiology 2004;7:78-84.
[10] Garmory HS, Griffin KF, Leary SE, et al. The effect of recombinant plasmids on in vivo colonisation of Salmonella enterica serovar Typhimurium strains is not reflected by in vitro cellular invasion assays. Vaccine 2002;20:3239-3243.
[11] Dunstan SJ, Simmons CP, Strugnell RA. In vitro and in vivo stability of recombinant plasmids in a vaccine strain of Salmonella enterica var. Typhimurium. FEMS immunology and medical microbiology 2003;37:l 11-119.
[12] Boucrot E, Henry T, Borg JP, et al. The intracellular fate of Salmonella depends on the recruitment of kinesin. Science 2005;308:1174-1178.
[13] Beuzon CR, Meresse S, Unsworth KE, et al. Salmonella maintains the integrity of its intracellular vacuole through the action of SifA. The EMBO journal 2000;19:3235- 3249.
[14] Beuzon CR, Salcedo SP, Holden DW. Growth and killing of a Salmonella enterica serovar Typhimurium sifA mutant strain in the cytosol of different host cell lines. Microbiology (Reading, England) 2002;148:2705-2715.
[15] Wick MJ, Harding CV, Normark SJ, et al. Parameters that influence the efficiency ofprocessing antigenic epitopes expressed in Salmonella typhimurium. Infection and immunity 1994;62:4542-4548.
[16] Covone MG, Brocchi M, Palla E, et al. Levels of expression and immunogenicity of attenuated Salmonella enterica serovar typhimurium strains expressing Escherichia coli mutant heat-labile enterotoxin. Infection and immunity 1998;66:224-231.
[17] Galan JE, Nakayama K, Curtiss R, 3rd. Cloning and characterization of the asd gene of Salmonella typhimurium: use in stable maintenance of recombinant plasmids in Salmonella vaccine strains. Gene 1990;94:29-35.
[2]Hardy RR.B-1 B cells:development,selection,natural autoantibody and leukemia.Current opinion in immunology 2006;18:547-555.
[3]Kawai T,Akira S.Innate immune recognition of viral infection.Nature immunology 2006;7:131-137.
[4]Adkins B,Leclerc C,Marshall-Clarke S.Neonatal adaptive immunity comes of age.Nature reviews 2004;4:553-564.
[5]Siegrist CA.Neonatal and early life vaccinology.Vaccine 2001;19:3331-3346.
[6]Wu L.T lineage progenitors:the earliest steps en route to T lymphocytes.Current opinion in immunology 2006;18:121-126.
[7]Liu C,Saito F,Liu Z,et al.Coordination between CCR7- and CCR9-mediated chemokine signals in prevascular fetal thymus colonization.Blood 2006;108:2531-2539.
[8]Rossi FM,Corbel SY,Merzaban JS,et al.Recruitment of adult thymic progenitors is regulated by P-selectin and its ligand PSGL-1.Nature immunology 2005;6:626-634.
[9]Pui JC,Allman D,Xu L,et al.Notchl expression in early lymphopoiesis influences B versus T lineage determination.Immunity 1999;11:299-308.
[10]Sambandam A,Maillard I,Zediak VP,et al.Notch signaling controls the generation and differentiation of early T lineage progenitors.Nature immunology 2005;6:663-670.
[11]Carding SR,Egan PJ.Gammadelta T cells:functional plasticity and heterogeneity.Nature reviews 2002;2:336-345.
[12]Konigshofer Y,Chien YH.Gammadelta T cells-innate immune lymphocytes?Current opinion in immunology 2006;18:527-533.
[13]Farrar JD,Asnagli H,Murphy KM.T helper subset development:roles of instruction,selection,and transcription.The Journal of clinical investigation 2002;109:431-435.
[14]Weaver CT,Harrington LE,Mangan PR,et al.Th17:an effector CD4 T cell lineage with regulatory T cell ties.Immunity 2006;24:677-688.
[15]Adkins B,Hamilton K.Freshly isolated,murine neonatal T cells produce IL-4 in response to anti-CD3 stimulation.J Immunol 1992;149:3448-3455.
[16]Ivanov,II,McKenzie BS,Zhou L,et al.The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+T helper cells.Cell 2006;126:1121-1133.
[17]Carrier Y,Yuan J,Kuchroo VK,et al.Th3 cells in peripheral tolerance.I.Induction of Foxp3-positive regulatory T cells by Th3 cells derived from TGF-beta T cell-transgenic mice.J Immunol 2007;178:179-185.
[18]Carrier Y,Yuan J,Kuchroo VK,et al.Th3 cells in peripheral tolerance.II.TGF-beta-transgenic Th3 cells rescue IL-2-deficient mice from autoimmunity.J Immunol 2007;178:172-178.
[19]Adkins B,Bu Y,Guevara P.Murine neonatal CD4+ lymph node cells are highly deficient in the development of antigen-specific Th1 function in adoptive adult hosts.J Immunol 2002;169:4998-5004.
[20]Adkins B,Chun K,Hamilton K,et al.Naive murine neonatal T cells undergo apoptosis in response to primary stimulation.J Immunol 1996;157:1343-1349.
[21]Li L,Lee HH,Bell JJ,et al.IL-4 utilizes an alternative receptor to drive apoptosis of Th1 cells and skews neonatal immunity toward Th2.Immunity 2004;20:429-440.
[22]Gao Q,Chen N,Rouse TM,et al.The role of interleukin-4 in the induction phase of allogeneic neonatal tolerance.Transplantation 1996;62:1847-1854.
[23]Donckier V,Flamand V,Desalle F,et al.IL-12 prevents neonatal induction of transplantation tolerance in mice.European journal of immunology 1998;28:1426-1430.
[24]Adkins B.Developmental regulation of the intrathymic T cell precursor population.J Immunol 1991;146:1387-1393.
[25]Ikuta K,Kina T,MacNeil I,et al.A developmental switch in thymic lymphocyte maturation potential occurs at the level of hematopoietic stem cells.Cell 1990;62:863-874.
[26]Adkins B.Peripheral CD4+ lymphocytes derived from fetal versus adult thymic precursors differ phenotypically and functionally.J Immunol 2003;171:5157-5164.
[27]Marchant A,Goetghebuer T,Ota MO,et al.Newborns develop a Th1-type immune response to Mycobacterium bovis bacillus Calmette-Guerin vaccination.J Immunol 1999;163:2249-2255.
[28]Vekemans J,Amedei A,Ota MO,et al.Neonatal bacillus Calmette-Guerin vaccination induces adult-like IFN-gamma production by CD4+ T lymphocytes.European journal of immunology 2001;31:1531-1535.
[29]Kollmann TR,Reikie B,Blimkie D,et al.Induction of Protective Immunity to Listeria monocytogenes in Neonates.J Immunol 2007;178:3695-3701.
[30]Martinez X,Brandt C,Saddallah F,et al.DNA immunization circumvents deficient induction of T helper type 1 and cytotoxic T lymphocyte responses in neonates and during early life.Proceedings of the National Academy of Sciences of the United States of America 1997;94:8726-8731.
[31]Forsthuber T,Yip HC,Lehmann PV.Induction of TH1 and TH2 immunity in neonatal mice.Science 1996;271:1728-1730.
[32]Sun CM,Deriaud E,Leclerc C,et al.Upon TLR9 signaling,CD5+ B cells control the IL-12-dependent Th1-priming capacity of neonatal DCs.Immunity 2005;22:467-477.
[33]Sakaguchi S,Sakaguchi N,Asano M,et al.Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains(CD25).Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.J Immunol 1995;155:1151-1164.
[34]Fontenot JD,Rasmussen JP,Williams LM,et al.Regulatory T cell lineage specification by the forkhead transcription factor foxp3.Immunity 2005;22:329-341.
[35]Hori S,Nomura T,Sakaguchi S.Control of regulatory T cell development by the transcription factor Foxp3.Science 2003;299:1057-1061.
[36]Fontenot JD,Gavin MA,Rudensky AY.Foxp3 programs the development and function of CD4+CD25+ regulatory T cells.Nature immunology 2003;4:330-336.
[37]Fontenot JD,Dooley JL,Farr AG,et al.Developmental regulation of Foxp3expression during ontogeny.The Journal of experimental medicine 2005;202:901-906.
[38]Kim JM,Rasmussen JP,Rudensky AY.Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice.Nature immunology 2007;8:191-197.
[39]Lahl K,Loddenkemper C,Drouin C,et al.Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease.The Journal of experimental medicine 2007;204:57-63.
[40]Pihlgren M,Tougne C,Bozzotti P,et al.Unresponsiveness to lymphoid-mediated signals at the neonatal follicular dendritic cell precursor level contributes to delayed germinal center induction and limitations of neonatal antibody responses to T- dependent antigens. J Immunol 2003; 170:2824-2832.
[41] Pihlgren M, Friedli M, Tougne C, et al. Reduced ability of neonatal and early-life bone marrow stromal cells to support plasmablast survival. J Immunol 2006;176:165- 172.
[42] Pihlgren M, Tougne C, Schallert N, et al. CpG-motifs enhance initial and sustained primary tetanus-specific antibody secreting cell responses in spleen and bone marrow, but are more effective in adult than in neonatal mice. Vaccine 2003;21:2492-2499.
[43] Gramzinski RA, Millan CL, Obaldia N, et al. Immune response to a hepatitis B DNA vaccine in Aotus monkeys: a comparison of vaccine formulation, route, and method of administration. Molecular medicine (Cambridge, Mass 1998;4:109-118.
[44] Kovarik J, Bozzotti P, Love-Homan L, et al. CpG oligodeoxynucleotides can circumvent the Th2 polarization of neonatal responses to vaccines but may fail to fully redirect Th2 responses established by neonatal priming. J Immunol 1999;162:1611- 1617.
[45] Edwards MS. Complement in neonatal infections: an overview. Pediatric infectious disease 1986;5:S168-170.
[46] Pihlgren M, Fulurija A, Villiers MB, et al. Influence of complement C3 amount on IgG responses in early life: immunization with C3b-conjugated antigen increases murine neonatal antibody responses. Vaccine 2004;23:329-335.
[47] Pihlgren M, Schallert N, Tougne C, et al. Delayed and deficient establishment of the long-term bone marrow plasma cell pool during early life. European journal of immunology 2001;31:939-946.
[48] Mancuso G, Midiri A, Beninati C, et al. Dual role of TLR2 and myeloid differentiation factor 88 in a mouse model of invasive group B streptococcal disease. J Immunol 2004; 172:6324-6329.
[49] Hoffman JA, Mason EO, Schutze GE, et al. Streptococcus pneumoniae infections in the neonate. Pediatrics 2003;112:1095-1102.
[50] Kovarik J, Bozzotti P, Tougne C, et al. Adjuvant effects of CpG oligodeoxynucleotides on responses against T-independent type 2 antigens. Immunology 2001; 102:67-76.
[51] Weller S, Reynaud CA, Weill JC. Vaccination against encapsulated bacteria in humans: paradoxes. Trends in immunology 2005;26:85-89.
[52] Shortman K, Naik SH. Steady-state and inflammatory dendritic-cell development. Nature reviews 2007;7:19-30.
[53] Karsunky H, Merad M, Cozzio A, et al. Flt3 ligand regulates dendritic cell development from Flt3+ lymphoid and myeloid-committed progenitors to Flt3+ dendritic cells in vivo. The Journal of experimental medicine 2003;198:305-313.
[54] D'Amico A, Wu L. The early progenitors of mouse dendritic cells and plasmacytoid predendritic cells are within the bone marrow hemopoietic precursors expressing Flt3. The Journal of experimental medicine 2003; 198:293-303.
[55] Naik SH, Metcalf D, van Nieuwenhuijze A, et al. Intrasplenic steady-state dendritic cell precursors that are distinct from monocytes. Nature immunology 2006;7:663-671.
[56] Cheng P, Nefedova Y, Corzo CA, et al. Regulation of dendritic-cell differentiation by bone marrow stroma via different Notch ligands. Blood 2007;109:507-515.
[57] Olivier A, Lauret E, Gonin P, et al. The Notch ligand delta-1 is a hematopoietic development cofactor for plasmacytoid dendritic cells. Blood 2006;107:2694-2701.
[58] Dontje W, Schotte R, Cupedo T, et al. Delta-like 1-induced Notchl signaling regulates the human plasmacytoid dendritic cell versus T-cell lineage decision through control of GATA-3 and Spi-B. Blood 2006; 107:2446-2452.
[59] Allman D, Dalod M, Asselin-Paturel C, et al. Ikaros is required for plasmacytoid dendritic cell differentiation. Blood 2006; 108:4025-4034.
[60] Wolber FM, Leonard E, Michael S, et al. Roles of spleen and liver in development of the murine hematopoietic system. Experimental hematology 2002;30:1010-1019.
[61] Dakic A, Shao QX, D'Amico A, et al. Development of the dendritic cell system during mouse ontogeny. J Immunol 2004;172:1018-1027.
[62] Sun CM, Fiette L, Tanguy M, et al. Ontogeny and innate properties of neonatal dendritic cells. Blood 2003;102:585-591.
[63] Dadaglio G, Sun CM, Lo-Man R, et al. Efficient in vivo priming of specific cytotoxic T cell responses by neonatal dendritic cells. J Immunol 2002;168:2219-2224.
[64] De Wit D, Olislagers V, Goriely S, et al. Blood plasmacytoid dendritic cell responses to CpG oligodeoxynucleotides are impaired in human newborns. Blood 2004;103:1030-1032.
[65] Aldebert D, Diallo M, Niang M, et al. Differences in circulating dendritic cell subtypes in peripheral, placental and cord blood in African pregnant women. Journal of reproductive immunology 2007 ;73:11-19.
[66] Darmochwal-Kolarz D, Rolinski J, Buczkowski J, et al. CD1c(+) immature myeloid dendritic cells are predominant in cord blood of healthy neonates. Immunology letters 2004;91:71-74.
[67] Levy O, Zarember KA, Roy RM, et al. Selective impairment of TLR-mediated innate immunity in human newborns: neonatal blood plasma reduces monocyte TNF-alpha induction by bacterial lipopeptides, lipopolysaccharide, and imiquimod, but preserves the response to R-848. J Immunol 2004; 173:4627-4634.
[68] Upham JW, Lee PT, Holt BJ, et al. Development of interleukin-12-producing capacity throughout childhood. Infection and immunity 2002;70:6583-6588.
[69] Lu CY, Beller DI, Unanue ER. During ontogeny, la-bearing accessory cells are found early in the thymus but late in the spleen. Proceedings of the National Academy of Sciences of the United States of America 1980;77:1597-1601.
[70] Muthukkumar S, Goldstein J, Stein KE. The ability of B cells and dendritic cells to present antigen increases during ontogeny. J Immunol 2000;165:4803-4813.
[71] Goriely S, Van Lint C, Dadkhah R, et al. A defect in nucleosome remodeling prevents IL-12(p35) gene transcription in neonatal dendritic cells. The Journal of experimental medicine 2004;199:1011-1016.
[72] Gramzinski RA, Doolan DL, Sedegah M, et al. Interleukin-12- and gamma interferon- dependent protection against malaria conferred by CpG oligodeoxynucleotide in mice. Infection and immunity 2001;69:1643-1649.
[73] Karlsson H, Hessle C, Rudin A. Innate immune responses of human neonatal cells to bacteria from the normal gastrointestinal flora. Infection and immunity 2002;70:6688- 6696.
[74] Levy O, Coughlin M, Cronstein BN, et al. The Adenosine System Selectively Inhibits TLR-Mediated TNF-{alpha} Production in the Human Newborn. J Immunol 2006;177:1956-1966.
[75] Gold MC, Donnelly E, Cook MS, et al. Purified neonatal plasmacytoid dendritic cells overcome intrinsic maturation defect with TLR agonist stimulation. Pediatric research 2006;60:34-37.
[76] Salio M, Dulphy N, Renneson J, et al. Efficient priming of antigen-specific cytotoxic T lymphocytes by human cord blood dendritic cells. International immunology 2003;15:1265-1273.
[77]Barrios C,Brandt C,Bemey M,et al.Partial correction of the TH2/TH1 imbalance in neonatal murine responses to vaccine antigens through selective adjuvant effects.European journal of immunology 1996;26:2666-2670.
[78]Kovarik J,Martinez X,Pihlgren M,et al.Limitations of in vivo IL-12supplementation strategies to induce Th1 early life responses to model viral and bacterial vaccine antigens.Virology 2000;268:122-131.
[79]Lotz M,Gutle D,Walther S,et al.Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells.The Journal of experimental medicine 2006;203:973-984.
[80]Genovese F,Mancuso G,Cuzzola M,et al.Role of IL-10 in a neonatal mouse listeriosis model.J Immunol 1999;163:2777-2782.
[81]Ito S,Ishii KJ,Gursel M,et al.CpG oligodeoxynucleotides enhance neonatal resistance to Listeria infection.J Immunol 2005;174:777-782.
[82]Pedras-Vasconcelos JA,Goucher D,Puig M,et al.CpG oligodeoxynucleotides protect newborn mice from a lethal challenge with the neurotropic Tacaribe arenavirus.J Immunol 2006;176:4940-4949.
[83]Hardy RR,Hayakawa K.B cell development pathways.Annual review of immunology 2001;19:595-621.
[84]Montecino-Rodriguez E,Dorshkind K.New perspectives in B-1 B cell development and function.Trends in immunology 2006;27:428-433.
[85]Kearney JF.Innate-like B cells.Springer seminars in immunopathology 2005;26:377-383.
[86]Rumfelt LL,Zhou Y,Rowley BM,et al.Lineage specification and plasticity in CD19-early B cell precursors.The Journal of experimental medicine 2006;203:675-687.
[87]Solvason N,Lehuen A,Keamey JF.An embryonic source of Ly1 but not conventional B cells.International immunology 1991;3:543-550.
[88]Hayakawa K,Hardy RR,Herzenberg LA,et al.Progenitors for Ly-1 B cells are distinct from progenitors for other B cells.The Journal of experimental medicine 1985;161:1554-1568.
[89]Kantor AB,Stall AM,Adams S,et al.Differential development of progenitor activity for three B-cell lineages.Proceedings of the National Academy of Sciences of the United States of America 1992;89:3320-3324.
[90]Hardy RR,Hayakawa K.A developmental switch in B lymphopoiesis.Proceedings of the National Academy of Sciences of the United States of America 1991;88:11550-11554.
[91]Godin IE,Garcia-Porrero JA,Coutinho A,et al.Para-aortic splanchnopleura from early mouse embryos contains B1a cell progenitors.Nature 1993;364:67-70.
[92]Montecino-Rodriguez E,Leathers H,Dorshkind K.Identification of a B-1 B cell-specified progenitor.Nature immunology 2006;7:293-301.
[93]Cong YZ,Rabin E,Wortis HH.Treatment of murine CD5- B cells with anti-Ig,but not LPS,induces surface CD5:two B-cell activation pathways.International immunology 1991;3:467-476.
[94]Wortis HH,Teutsch M,Higer M,et al.B-cell activation by crosslinking of surface IgM or ligation of CD40 involves alternative signal pathways and results in different B-cell phenotypes.Proceedings of the National Academy of Sciences of the United States of America 1995;92:3348-3352.
[95]Berland R,Wortis HH.Origins and functions of B-1 cells with notes on the role of CD5.Annual review of immunology 2002;20:253-300.
[96]Hayakawa K,Asano M,Shinton SA,et al.Positive selection of natural autoreactive B cells.Science 1999;285:113-116.
[97] Hayakawa K, Hardy RR, Stall AM, et al. Immunoglobulin-bearing B cells reconstitute and maintain the murine Ly-1 B cell lineage. European journal of immunology 1986;16:1313-1316.
[98] Wen L, Brill-Dashoff J, Shinton SA, et al. Evidence of marginal-zone B cell-positive selection in spleen. Immunity 2005;23:297-308.
[99] Martin F, Kearney JF. Positive selection from newly formed to marginal zone B cells depends on the rate of clonal production, CD19, and btk. Immunity 2000; 12:39-49.
[100] Godin I, Dieterlen-Lievre F, Cumano A. Emergence of multipotent hemopoietic cells in the yolk sac and paraaortic splanchnopleura in mouse embryos, beginning at 8.5 days postcoitus. Proceedings of the National Academy of Sciences of the United States of America 1995;92:773-777.
[101] Sugiyama D, Ogawa M, Nakao K, et al. B cell potential can be obtained from pre- circulatory yolk sac, but with low frequency. Developmental biology 2007;301.53-61.
[102] de Andres B, Gonzalo P, Minguet S, et al. The first 3 days of B-cell development in the mouse embryo. Blood 2002;100:4074-4081.
[103] Li YS, Hayakawa K, Hardy RR. The regulated expression of B lineage associated genes during B cell differentiation in bone marrow and fetal liver. The Journal of experimental medicine 1993; 178:951-960.
[104] Feeney AJ. Lack of N regions in fetal and neonatal mouse immunoglobulin V-D-J junctional sequences. The Journal of experimental medicine 1990; 172:1377-1390.
[105] Feeney AJ. Predominance of VH-D-JH junctions occurring at sites of short sequence homology results in limited junctional diversity in neonatal antibodies. J Immunol 1992; 149:222-229.
[106] Masmoudi H, Mota-Santos T, Huetz F, et al. All T15 Id-positive antibodies (but not the majority of VHT15+ antibodies) are produced by peritoneal CD5+ B lymphocytes. International immunology 1990;2:515-520.
[107] Briles DE, Forman C, Hudak S, et al. Anti-phosphorylcholine antibodies of the T15 idiotype are optimally protective against Streptococcus pneumoniae. The Journal of experimental medicine 1982;156:1177-1185.
[108] Benedict CL, Kearney JF. Increased junctional diversity in fetal B cells results in a loss of protective anti-phosphorylcholine antibodies in adult mice. Immunity 1999;10:607-617.
[109] Hardy RR. B-1 B cell development. J Immunol 2006; 177:2749-2754.
[110] Arnold LW, Pennell CA, McCray SK, et al. Development of B-1 cells: segregation of phosphatidyl choline-specific B cells to the B-1 population occurs after immunoglobulin gene expression. The Journal of experimental medicine 1994;179:1585-1595.
[111] Wasserman R, Li YS, Shinton SA, et al. A novel mechanism for B cell repertoire maturation based on response by B cell precursors to pre-B receptor assembly. The Journal of experimental medicine 1998;187:259-264.
[112] Hayakawa K, Asano M, Shinton SA, et al. Positive selection of anti-thy-1 autoreactive B-1 cells and natural serum autoantibody production independent from bone marrow B cell development. The Journal of experimental medicine 2003;197:87-99.
[113] Hayakawa K, Tarlinton D, Hardy RR. Absence of MHC class II expression distinguishes fetal from adult B lymphopoiesis in mice. J Immunol 1994; 152:4801- 4807.
[114] Lam KP, Stall AM. Major histocompatibility complex class II expression distinguishes two distinct B cell developmental pathways during ontogeny. The Journal of experimental medicine 1994;180:507-516.
[115] Tung JW, Mrazek MD, Yang Y, et al. Phenotypically distinct B cell development pathways map to the three B cell lineages in the mouse. Proceedings of the National Academy of Sciences of the United States of America 2006;103:6293-6298.
[116] Kantor AB, Merrill CE, Herzenberg LA, et al. An unbiased analysis of V(H)-D-J(H) sequences from B-1a, B-1b, and conventional B cells. J Immunol 1997;158:1175- 1186.
[117] Lalor PA, Herzenberg LA, Adams S, et al. Feedback regulation of murine Ly-1 B cell development. European journal of immunology 1989;19:507-513.
[118] Carvalho TL, Mota-Santos T, Cumano A, et al. Arrested B lymphopoiesis and persistence of activated B cells in adult interleukin 7(-/)- mice. The Journal of experimental medicine 2001;194:1141-1150.
[119] Miller JP, Izon D, DeMuth W, et al. The earliest step in B lineage differentiation from common lymphoid progenitors is critically dependent upon interleukin 7. The Journal of experimental medicine 2002; 196:705-711.
[120] von Freeden-Jeffry U, Vieira P, Lucian LA, et al. Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine. The Journal of experimental medicine 1995; 181:1519-1526.
[121] Dias S, Silva H, Jr., Cumano A, et al. Interleukin-7 is necessary to maintain the B cell potential in common lymphoid progenitors. The Journal of experimental medicine 2005 ;201:971-979.
[122] Vosshenrich CA, Cumano A, Muller W, et al. Pre-B cell receptor expression is necessary for thymic stromal lymphopoietin responsiveness in the bone marrow but not in the liver environment. Proceedings of the National Academy of Sciences of the United States of America 2004;101:11070-11075.
[123] Park LS, Martin U, Garka K, et al. Cloning of the murine thymic stromal lymphopoietin (TSLP) receptor: Formation of a functional heteromeric complex requires interleukin 7 receptor. The Journal of experimental medicine 2000; 192:659- 670.
[124] Ziegler SF, Liu YJ. Thymic stromal lymphopoietin in normal and pathogenic T cell development and function. Nature immunology 2006;7:709-714.
[125] Vosshenrich CA, Cumano A, Muller W, et al. Thymic stromal-derived lymphopoietin distinguishes fetal from adult B cell development. Nature immunology 2003;4:773- 779.
[126] Sitnicka E, Brakebusch C, Martensson IL, et al. Complementary signaling through flt3 and interleukin-7 receptor alpha is indispensable for fetal and adult B cell genesis. The Journal of experimental medicine 2003;198:1495-1506.
[127] Lyman SD, Jacobsen SE. c-kit ligand and Flt3 ligand: stem/progenitor cell factors with overlapping yet distinct activities. Blood 1998;91:1101-1134.
[128] McKenna HJ, Stocking KL, Miller RE, et al. Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic progenitor cells, dendritic cells, and natural killer cells. Blood 2000;95:3489-3497.
[129] Mackarehtschian K, Hardin JD, Moore KA, et al. Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors. Immunity 1995;3:147-161.
[130] Sitnicka E, Bryder D, Theilgaard-Monch K, et al. Key role of flt3 ligand in regulation of the common lymphoid progenitor but not in maintenance of the hematopoietic stem cell pool. Immunity 2002;17:463-472.
[131] Kikuchi K, Kondo M. Developmental switch of mouse hematopoietic stem cells from fetal to adult type occurs in bone marrow after birth. Proceedings of the National Academy of Sciences of the United States of America 2006; 103:17852-17857.
[132] Coulomb-L'Hermin A, Amara A, Schiff C, et al. Stromal cell-derived factor 1 (SDF-1) and antenatal human B cell lymphopoiesis: expression of SDF-1 by mesothelial cells and biliary ductal plate epithelial cells. Proceedings of the National Academy of Sciences of the United States of America 1999;96:8585-8590.
[133] Nagasawa T, Kikutani H, Kishimoto T. Molecular cloning and structure of a pre-B- cell growth-stimulating factor. Proceedings of the National Academy of Sciences of the United States of America 1994;91:2305-2309.
[134] Ma Q, Jones D, Springer TA. The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment. Immunity 1999; 10:463-471.
[135] Foussat A, Balabanian K, Amara A, et al. Production of stromal cell-derived factor 1 by mesothelial cells and effects of this chemokine on peritoneal B lymphocytes. European journal of immunology 2001;31:350-359.
[136] Ma Q, Jones D, Borghesani PR, et al. Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proceedings of the National Academy of Sciences of the United States of America 1998;95:9448-9453.
[137] Nagasawa T, Hirota S, Tachibana K, et al. Defects of B-cell lymphopoiesis and bone- marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 1996;382:635-638.
[138] Balabanian K, Lagane B, Infantino S, et al. The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. The Journal of biological chemistry 2005;280:35760-35766.
[139] Tominaga A, Takaki S, Koyama N, et al. Transgenic mice expressing a B cell growth and differentiation factor gene (interleukin 5) develop eosinophilia and autoantibody production. The Journal of experimental medicine 1991; 173:429-437.
[140] Kopf M, Brombacher F, Hodgkin PD, et al. IL-5-deficient mice have a developmental defect in CD5+ B-1 cells and lack eosinophilia but have normal antibody and cytotoxic T cell responses. Immunity 1996;4:15-24.
[141] Yoshida T, Ikuta K, Sugaya H, et al. Defective B-1 cell development and impaired immunity against Angiostrongylus cantonensis in IL-5R alpha-deficient mice. Immunity 1996;4:483-494.
[142] Hayakawa K, Hardy RR, Parks DR, et al. The "Ly-1 B" cell subpopulation in normal immunodefective, and autoimmune mice. The Journal of experimental medicine 1983;157:202-218.
[143] Wen L, Shinton SA, Hardy RR, et al. Association of B-1 B cells with follicular dendritic cells in spleen. J Immunol 2005;174:6918-6926.
[144] Ansel KM, Harris RB, Cyster JG. CXCL13 is required for B1 cell homing, natural antibody production, and body cavity immunity. Immunity 2002; 16:67-76.
[145] Hopken UE, Achtman AH, Kruger K, et al. Distinct and overlapping roles of CXCR5 and CCR7 in B-1 cell homing and early immunity against bacterial pathogens. J Leukoc Biol 2004;76:709-718.
[146] Ha SA, Tsuji M, Suzuki K, et al. Regulation of B1 cell migration by signals through Toll-like receptors. The Journal of experimental medicine 2006;203:2541-2550.
[147] Balabanian K, Foussat A, Bouchet-Delbos L, et al. Interleukin-10 modulates the sensitivity of peritoneal B lymphocytes to Chemokines with opposite effects on stromal cell-derived factor-1 and B-lymphocyte chemoattractant. Blood 2002;99:427- 436.
[148] Kuhn R, Lohler J, Rennick D, et al. Interleukin- 10-deficient mice develop chronic enterocolitis. Cell 1993;75:263-274.
[149] Murakami M, Tsubata T, Shinkura R, et al. Oral administration of lipopolysaccharides activates B-1 cells in the peritoneal cavity and lamina propria of the gut and induces autoimmune symptoms in an autoantibody transgenic mouse. The Journal of experimental medicine 1994; 180:111 -121.
[150] Macpherson AJ, Uhr T. Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science 2004;303:1662-1665.
[151] Fagarasan S, Shinkura R, Kamata T, et al. Alymphoplasia (aly)-type nuclear factor kappaB-inducing kinase (NIK) causes defects in secondary lymphoid tissue chemokine receptor signaling and homing of peritoneal cells to the gut-associated lymphatic tissue system. The Journal of experimental medicine 2000; 191:1477-1486.
[152] Mora JR, Iwata M, Eksteen B, et al. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 2006;314:1157-1160.
[153] Baumgarth N, Tung JW, Herzenberg LA. Inherent specificities in natural antibodies: a key to immune defense against pathogen invasion. Springer seminars in immunopathology 2005;26:347-362.
[154] Tumang JR, Frances R, Yeo SG, et al. Spontaneously Ig-secreting B-1 cells violate the accepted paradigm for expression of differentiation-associated transcription factors. J Immunol 2005;174:3173-3177.
[155] Savitsky D, Calame K. B-1 B lymphocytes require Blimp-1 for immunoglobulin secretion. The Journal of experimental medicine 2006;203:2305-2314.
[156] Briles DE, Claflin JL, Schroer K, et al. Mouse Igg3 antibodies are highly protective against infection with Streptococcus pneumoniae. Nature 1981;294:88-90.
[157] Briles DE, Nahm M, Schroer K, et al. Antiphosphocholine antibodies found in normal mouse serum are protective against intravenous infection with type 3 streptococcus pneumoniae. The Journal of experimental medicine 1981;153:694-705.
[158] Ochsenbein AF, Fehr T, Lutz C, et al. Control of early viral and bacterial distribution and disease by natural antibodies. Science 1999;286:2156-2159.
[159] Baumgarth N, Chen J, Herman OC, et al. The role of B-1 and B-2 cells in immune protection from influenza virus infection. Current topics in microbiology and immunology 2000;252:163-169.
[160] Baumgarth N, Herman OC, Jager GC, et al. Innate and acquired humoral immunities to influenza virus are mediated by distinct arms of the immune system. Proceedings of the National Academy of Sciences of the United States of America 1999;96:2250- 2255.
[161] Boes M, Prodeus AP, Schmidt T, et al. A critical role of natural immunoglobulin M in immediate defense against systemic bacterial infection. The Journal of experimental medicine 1998;188:2381-2386.
[162] Reid RR, Prodeus AP, Khan W, et al. Endotoxin shock in antibody-deficient mice: unraveling the role of natural antibody and complement in the clearance of lipopolysaccharide. J Immunol 1997; 159:970-975.
[163] Shaw PX, Goodyear CS, Chang MK, et al. The autoreactivity of anti- phosphorylcholine antibodies for atherosclerosis-associated neo-antigens and apoptotic cells. J Immunol 2003;170:6151-6157.
[164] Binder CJ, Silverman GJ. Natural antibodies and the autoimmunity of atherosclerosis. Springer seminars in immunopathology 2005;26:385-404.
[165] Murakami M, Yoshioka H, Shirai T, et al. Prevention of autoimmune symptoms in autoimmune-prone mice by elimination of B-1 cells. International immunology 1995;7:877-882.
[166] Steinberg BJ, Smathers PA, Frederiksen K, et al. Ability of the xid gene to prevent autoimmunity in (NZB X NZW)F1 mice during the course of their natural history, after polyclonal stimulation, or following immunization with DNA. The Journal of clinical investigation 1982;70:587-597.
[167] Kroese FG, Butcher EC, Stall AM, et al. Many of the IgA producing plasma cells in murine gut are derived from self-replenishing precursors in the peritoneal cavity. International immunology 1989;l:75-84.
[168] Kroese FG, Butcher EC, Stall AM, et al. A major peritoneal reservoir of precursors for intestinal IgA plasma cells. Immunol Invest 1989; 18:47-58.
[169] Macpherson AJ, Gatto D, Sainsbury E, et al. A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. Science 2000;288:2222-2226.
[170] Snider DP, Liang H, Switzer I, et al. IgA production in MHC class H-deficient mice is primarily a function of B-1a cells. International immunology 1999;11:191-198.
[171] Bergqvist P, Gardby E, Stensson A, et al. Gut IgA class switch recombination in the absence of CD40 does not occur in the lamina propria and is independent of germinal centers. J Immunol 2006; 177:7772-7783.
[172] de Waard R, Dammers PM, Tung JW, et al. Presence of germline and full-length IgA RNA transcripts among peritoneal B-1 cells. Developmental immunology 1998;6:81- 87.
[173] Binder CJ, Horkko S, Dewan A, et al. Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL. Nature medicine 2003;9:736-743.
[174] Martin F, Oliver AM, Kearney JF. Marginal zone and B1 B cells unite in the early response against T-independent blood-borne particulate antigens. Immunity 2001;14:617-629.
[175] Forster I, Rajewsky K. Expansion and functional activity of Ly-1+ B cells upon transfer of peritoneal cells into allotype-congenic, newborn mice. European journal of immunology 1987; 17:521-528.
[176] Hayakawa K, Hardy RR, Honda M, et al. Ly-1 B cells: functionally distinct lymphocytes that secrete IgM autoantibodies. Proceedings of the National Academy of Sciences of the United States of America 1984;81.2494-2498.
[177] Lopes-Carvalho T, Kearney JF. Development and selection of marginal zone B cells. Immunological reviews 2004;197:192-205.
[178] Hsu MC, Toellner KM, Vinuesa CG, et al. B cell clones that sustain long-term plasmablast growth in T-independent extrafollicular antibody responses. Proceedings of the National Academy of Sciences of the United States of America 2006; 103:5905- 5910.
[179] Haas KM, Poe JC, Steeber DA, et al. B-1a and B-1b cells exhibit distinct developmental requirements and have unique functional roles in innate and adaptive immunity to S. pneumoniae. Immunity 2005;23:7-18.
[180] Alugupalli KR, Gerstein RM, Chen J, et al. The resolution of relapsing fever borreliosis requires IgM and is concurrent with expansion of B1b lymphocytes. J Immunol 2003;170:3819-3827.
[181] Alugupalli KR, Leong JM, Woodland RT, et al. B1b lymphocytes confer T cell- independent long-lasting immunity. Immunity 2004;21:379-390.
[182] Balazs M, Martin F, Zhou T, et al. Blood dendritic cells interact with splenic marginal zone B cells to initiate T-independent immune responses. Immunity 2002;17:341-352.
[183] Chelvarajan RL, Raithatha R, Venkataraman C, et al. CpG oligodeoxynucleotides overcome the unresponsiveness of neonatal B cells to stimulation with the thymus- independent stimuli anti-IgM and TNP-Ficoll. European journal of immunology 1999;29:2808-2818.
[184]Lenert P,Brummel R,Field EH,et al.TLR-9 activation of marginal zone B cells in lupus mice regulates immunity through increased IL-10 production.Journal of clinical immunology 2005;25:29-40.
[185]Burke F,Stagg AJ,Bedford PA,et al.IL-10-producing B220+CD11c- APC in mouse spleen.J Immunol 2004;173:2362-2372.
[186]O'Garra A,Chang R,Go N,et al.Ly-1 B(B-1) cells are the main source of B cell-derived interleukin 10.European journal of immunology 1992;22:711-717.
[187]Fillatreau S,Sweenie CH,McGeachy MJ,et al.B cells regulate autoimmunity by provision of IL-10.Nature immunology 2002;3:944-950.
[188]Mauri C,Gray D,Mushtaq N,et al.Prevention of arthritis by interleukin 10-producing B cells.The Journal of experimental medicine 2003;197:489-501.
[189]Mangan NE,Fallon RE,Smith P,et al.Helminth infection protects mice from anaphylaxis via IL-10-producing B cells.J Immunol 2004;173:6346-6356.
[190]Ishida H,Hastings R,Kearney J,et al.Continuous anti-interleukin 10 antibody administration depletes mice of Ly-1 B cells but not conventional B cells.The Journal of experimental medicine 1992;175:1213-1220.
[191]Peng B,Mehta NH,Femandes H,et al.Growth inhibition of malignant CD5+B(B-1)cells by antisense IL-10 oligonucleotide.Leukemia research 1995;19:159-167.
[192]Harris DP,Haynes L,Sayles PC,et al.Reciprocal regulation of polarized cytokine production by effector B and T cells.Nature immunology 2000;1:475-482.
[193]Harris DP,Goodrich S,Mohrs K,et al.Cutting edge:the development of IL-4-producing B cells(B effector 2 cells) is controlled by IL-4,IL-4 receptor alpha,and Th2 cells.J Immunol 2005;175:7103-7107.
[194]Harris DP,Goodrich S,Gerth AJ,et al.Regulation of IFN-gamma production by B effector 1 cells:essential roles for T-bet and the IFN-gamma receptor.J Immunol 2005;174:6781-6790.
[195]Akira S,Uematsu S,Takeuchi O.Pathogen recognition and innate immunity.Cell 2006;124:783-801.
[196]Akira S,Takeda K.Toll-like receptor signalling.Nature reviews 2004;4:499-511.
[197]Takaoka A,Yanai H,Kondo S,et al.Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors.Nature 2005;434:243-249.
[198]Hacker H,Redecke V,Blagoev B,et al.Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6.Nature 2006;439:204-207.
[199]Oganesyan G,Saha SK,Guo B,et al.Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response.Nature 2006;439:208-211.
[200]Kawai T,Sato S,Ishii KJ,et al.Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6.Nature immunology 2004;5:1061-1068.
[201]Uematsu S,Sato S,Yamamoto M,et al.Interleukin-1 receptor-associated kinase-1plays an essential role for Toll-like receptor(TLR)7- and TLR9-mediated interferon-{alpha}induction.The Journal of experimental medicine 2005;201:915-923.
[202]Kawai T,Adachi O,Ogawa T,et al.Unresponsiveness of MyD88-deficient mice to endotoxin.Immunity 1999;11:115-122.
[203]Kato H,Takeuchi O,Sato S,et al.Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses.Nature 2006;441:101-105.
[204]Hornung V,Ellegast J,Kim S,et al.5'-Triphosphate RNA is the ligand for RIG-I.Science 2006;314:994-997.
[205]Pichlmair A,Schulz O,Tan CP,et al.RIG-I-mediated antiviral responses to single-stranded RNA bearing 5'-phosphates.Science 2006;314:997-1001.
[206] Saito T, Hirai R, Loo YM, et al. Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2. Proceedings of the National Academy of Sciences of the United States of America 2007; 104:582-587.
[207] Fritz JH, Ferrero RL, Philpott DJ, et al. Nod-like proteins in immunity, inflammation and disease. Nature immunology 2006;7:1250-1257.
[208] Hsu YM, Zhang Y, You Y, et al. The adaptor protein CARD9 is required for innate immune responses to intracellular pathogens. Nature immunology 2007;8:198-205.
[209] Miao EA, Alpuche-Aranda CM, Dors M, et al. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf. Nature immunology 2006;7:569- 575.
[210] Franchi L, Amer A, Body-Malapel M, et al. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin lbeta in salmonella-infected macrophages. Nature immunology 2006;7:576-582.
[211] Molofsky AB, Byrne BG, Whitfield NN, et al. Cytosolic recognition of flagellin by mouse macrophages restricts Legionella pneumophila infection. The Journal of experimental medicine 2006;203:1093-1104.
[212] Robinson MJ, Sancho D, Slack EC, et al. Myeloid C-type lectins in innate immunity. Nature immunology 2006;7:1258-1265.
[213] Brown GD, Gordon S. Immune recognition. A new receptor for beta-glucans. Nature 2001;413:36-37.
[214] Gantner BN, Simmons RM, Canavera SJ, et al. Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor 2. The Journal of experimental medicine 2003; 197:1107-1117.
[215] Rogers NC, Slack EC, Edwards AD, et al. Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity 2005;22:507-517.
[216] Gross O, Gewies A, Finger K, et al. Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity. Nature 2006;442:651-656.
[217] Taylor PR, Tsoni SV, Willment JA, et al. Dectin-1 is required for beta-glucan recognition and control of fungal infection. Nature immunology 2007;8:31-38.
[218] Saijo S, Fujikado N, Furuta T, et al. Dectin-1 is required for host defense against Pneumocystis carinii but not against Candida albicans. Nature immunology 2007;8:39-46.
[219] Mansell A, Smith R, Doyle SL, et al. Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation. Nature immunology 2006;7:148-155.
[220] Fenner JE, Starr R, Cornish AL, et al. Suppressor of cytokine signaling 1 regulates the immune response to infection by a unique inhibition of type I interferon activity. Nature immunology 2006;7:33-39.
[221] An H, Zhao W, Hou J, et al. SHP-2 Phosphatase Negatively Regulates the TRIF Adaptor Protein-Dependent Type I Interferon and Proinflammatory Cytokine Production. Immunity 2006;25:919-928.
[222] Divanovic S, Trompette A, Atabani SF, et al. Negative regulation of Toll-like receptor 4 signaling by the Toll-like receptor homolog RP105. Nature immunology 2005;6:571-578.
[223] Wald D, Qin J, Zhao Z, et al. SIGIRR, a negative regulator of Toll-like receptor- interleukin 1 receptor signaling. Nature immunology 2003;4:920-927.
[224] Brint EK, Xu D, Liu H, et al. ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance. Nature immunology 2004;5:373-379.
[225] Burns K, Janssens S, Brissoni B, et al. Inhibition of interleukin 1 receptor/Toll-like receptor signaling through the alternatively spliced, short form of MyD88 is due to its failure to recruit IRAK-4. The Journal of experimental medicine 2003;197:263-268.
[226] Kobayashi K, Hernandez LD, Galan JE, et al. IRAK-M is a negative regulator of Toll- like receptor signaling. Cell 2002;110:191-202.
[227] Isaacs A, Lindenmann J. Virus interference. I. The interferon. Proceedings of the Royal Society of London Series B, Containing papers of a Biological character 1957;147:258-267.
[228] Theofilopoulos AN, Baccala R, Beutler B, et al. Type I interferons (alpha/beta) in immunity and autoimmunity. Annual review of immunology 2005;23:307-336.
[229] Ank N, West H, Paludan SR. IFN-lambda: novel antiviral cytokines. J Interferon Cytokine Res 2006;26:373-379.
[230] Honda K, Yanai H, Negishi H, et al. IRF-7 is the master regulator of type-I interferon- dependent immune responses. Nature 2005;434:772-777.
[231] Lee HK, Lund JM, Ramanathan B, et al. Autophagy-dependent viral recognition by plasmacytoid dendritic cells. Science 2007;315:1398-1401.
[232] Duramad O, Fearon KL, Chan JH, et al. IL-10 regulates plasmacytoid dendritic cell response to CpG-containing immunostimulatory sequences. Blood 2003;102:4487- 4492.
[233] Boonstra A, Rajsbaum R, Holman M, et al. Macrophages and myeloid dendritic cells, but not plasmacytoid dendritic cells, produce IL-10 in response to MyD88- and TRIF- dependent TLR signals, and TLR-independent signals. J Immunol 2006; 177:7551- 7558.
[234] Bave U, Vallin H, Alm GV, et al. Activation of natural interferon-alpha producing cells by apoptotic U937 cells combined with lupus IgG and its regulation by cytokines. Journal of autoimmunity 2001; 17:71-80.
[235] Palucka AK, Blanck JP, Bennett L, et al. Cross-regulation of TNF and IFN-alpha in autoimmune diseases. Proceedings of the National Academy of Sciences of the United States of America 2005;102:3372-3377.
[236] Bjorck P. Dendritic cells exposed to herpes simplex virus in vivo do not produce IFN- alpha after rechallenge with virus in vitro and exhibit decreased T cell alloreactivity. J Immunol 2004; 172:5396-5404.
[237] Kerkmann M, Costa LT, Richter C, et al. Spontaneous formation of nucleic acid-based nanoparticles is responsible for high interferon-alpha induction by CpG-A in plasmacytoid dendritic cells. The Journal of biological chemistry 2005;280:8086- 8093.
[238] Krieg AM. CpG motifs in bacterial DNA and their immune effects. Annual review of immunology 2002;20:709-760.
[239] Hartmann G, Battiany J, Poeck H, et al. Rational design of new CpG oligonucleotides that combine B cell activation with high IFN-alpha induction in plasmacytoid dendritic cells. European journal of immunology 2003;33:1633-1641.
[240] Marshall JD, Fearon K, Abbate C, et al. Identification of a novel CpG DNA class and motif that optimally stimulate B cell and plasmacytoid dendritic cell functions. Journal of leukocyte biology 2003 ;73:781-792.
[241] Honda K, Ohba Y, Yanai H, et al. Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Nature 2005;434:1035-1040.
[242] Guiducci C, Ott G, Chan JH, et al. Properties regulating the nature of the plasmacytoid dendritic cell response to Toll-like receptor 9 activation. The Journal of experimental medicine 2006.
[243] Mohty M, Vialle-Castellano A, Nunes JA, et al. IFN-alpha skews monocyte differentiation into Toll-like receptor 7-expressing dendritic cells with potent functional activities. J Immunol 2003;171:3385-3393.
[244] Gray RC, Kuchtey J, Harding CV. CpG-B ODNs potently induce low levels of IFN- {alpha} {beta} and induce IFN-{alpha} {beta}-dependent MHC-I cross-presentation in DCs as effectively as CpG-A and CpG-C ODNs. Journal of leukocyte biology 2007.
[245] Ishii KJ, Coban C, Kato H, et al. A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA. Nature immunology 2006;7.40-48.
[246] Stetson DB, Medzhitov R. Recognition of Cytosolic DNA activates an IRF3-dependent innate immune response. Immunity 2006;24:93-103.
[247] Honda K, Takaoka A, Taniguchi T. Type I interferon [corrected] gene induction by the interferon regulatory factor family of transcription factors. Immunity 2006;25:349- 360.
[248] van Boxel-Dezaire AH, Rani MR, Stark GR. Complex modulation of cell type- specific signaling in response to type I interferons. Immunity 2006;25:361-372.
[249] Stark GR, Kerr IM, Williams BR, et al. How cells respond to interferons. Annual review of biochemistry 1998;67:227-264.
[250] Pien GC, Nguyen KB, Malmgaard L, et al. A unique mechanism for innate cytokine promotion of T cell responses to viral infections. J Immunol 2002; 169:5827-5837.
[251] Nguyen KB, Cousens LP, Doughty LA, et al. Interferon alpha/beta-mediated inhibition and promotion of interferon gamma: STAT1 resolves a paradox. Nature immunology 2000; 1:70-76.
[252] Nguyen KB, Watford WT, Salomon R, et al. Critical role for STAT4 activation by type 1 interferons in the interferon-gamma response to viral infection. Science 2002;297:2063-2066.
[253] Bromberg JF, Horvath CM, Wen Z, et al. Transcriptionally active Statl is required for the antiproliferative effects of both interferon alpha and interferon gamma. Proceedings of the National Academy of Sciences of the United States of America 1996;93:7673-7678.
[254] Tanabe Y, Nishibori T, Su L, et al. Cutting edge: role of STAT1, STAT3, and STAT5 in IFN-alpha beta responses in T lymphocytes. J Immunol 2005;174:609-613.
[255] Wong LH, Sim H, Chatterjee-Kishore M, et al. Isolation and characterization of a human STAT1 gene regulatory element. Inducibility by interferon (IFN) types I and II and role of IFN regulatory factor-1. The Journal of biological chemistry 2002;277:19408-19417.
[256] Marrack P, Kappler J, Mitchell T. Type I interferons keep activated T cells alive. The Journal of experimental medicine 1999;189:521-530.
[257] Tough DF, Sun S, Sprent J. T cell stimulation in vivo by lipopolysaccharide (LPS). The Journal of experimental medicine 1997;185:2089-2094.
[258] Tough DF, Borrow P, Sprent J. Induction of bystander T cell proliferation by viruses and type I interferon in vivo. Science 1996;272:1947-1950.
[259] Curtsinger JM, Valenzuela JO, Agarwal P, et al. Type I IFNs provide a third signal to CD8 T cells to stimulate clonal expansion and differentiation. J Immunol 2005;174:4465-4469.
[260] Kolumam GA, Thomas S, Thompson LJ, et al. Type I interferons act directly on CD8 T cells to allow clonal expansion and memory formation in response to viral infection. The Journal of experimental medicine 2005;202:637-650.
[261] Hervas-Stubbs S, Rueda P, Lopez L, et al. Insect baculoviruses strongly potentiate adaptive immune responses by inducing type I IFN. J Immunol 2007;178:2361-2369.
[262] Le Bon A, Durand V, Kamphuis E, et al. Direct stimulation of T cells by type I IFN enhances the CD8+ T cell response during cross-priming. J Immunol 2006; 176:4682- 4689.
[263] Gil MP, Salomon R, Louten J, et al. Modulation of STAT1 protein levels: a mechanism shaping CD8 T-cell responses in vivo. Blood 2006; 107:987-993.
[264] Zhang X, Sun S, Hwang I, et al. Potent and selective stimulation of memory- phenotype CD8+ T cells in vivo by IL-15. Immunity 1998;8:591-599.
[265] Orange JS, Biron CA. Characterization of early IL-12, IFN-alphabeta, and TNF effects on antiviral state and NK cell responses during murine cytomegalovirus infection. J Immunol 1996; 156:4746-4756.
[266] Andoniou CE, van Dommelen SL, Voigt V, et al. Interaction between conventional dendritic cells and natural killer cells is integral to the activation of effective antiviral immunity. Nature immunology 2005;6:1011-1019.
[267] Nguyen KB, Salazar-Mather TP, Dalod MY, et al. Coordinated and distinct roles for IFN-alpha beta, IL-12, and IL-15 regulation of NK cell responses to viral infection. J Immunol 2002; 169:4279-4287.
[268] Braun D, Caramalho I, Demengeot J. IFN-alpha/beta enhances BCR-dependent B cell responses. International immunology 2002;14:411-419.
[269] Jego G, Palucka AK, Blanck JP, et al. Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6. Immunity 2003;19:225-234.
[270] Le Bon A, Thompson C, Kamphuis E, et al. Cutting edge: enhancement of antibody responses through direct stimulation of B and T cells by type I IFN. J Immunol 2006; 176:2074-2078.
[271] Litinskiy MB, Nardelli B, Hilbert DM, et al. DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL. Nature immunology 2002;3:822-829.
[272] Wang J, Lin Q, Langston H, et al. Resident bone marrow macrophages produce type 1 interferons that can selectively inhibit interleukin-7-driven growth of B lineage cells. Immunity 1995;3:475-484.
[273] Lin Q, Dong C, Cooper MD. Impairment of T and B cell development by treatment with a type I interferon. The Journal of experimental medicine 1998;187:79-87.
[274] Muller U, Steinhoff U, Reis LF, et al. Functional role of type I and type II interferons in antiviral defense. Science 1994;264:1918-1921.
[275] Binder D, Fehr J, Hengartner H, et al. Virus-induced transient bone marrow aplasia: major role of interferon-alphafteta during acute infection with the noncytopathic lymphocytic choriomeningitis virus. The Journal of experimental medicine 1997;185:517-530.
[276] Kadowaki N, Antonenko S, Lau JY, et al. Natural interferon alpha/beta-producing cells link innate and adaptive immunity. The Journal of experimental medicine 2000;192:219-226.
[277] Dalod M, Salazar-Mather TP, Malmgaard L, et al. Interferon alpha/beta and interleukin 12 responses to viral infections: pathways regulating dendritic cell cytokine expression in vivo. The Journal of experimental medicine 2002;195:517-528.
[278] Shinohara ML, Lu L, Bu J, et al. Osteopontin expression is essential for interferon- alpha production by plasmacytoid dendritic cells. Nature immunology 2006;7:498- 506.
[279] Asselin-Paturel C, Brizard G, Chemin K, et al. Type I interferon dependence of plasmacytoid dendritic cell activation and migration. The Journal of experimental medicine 2005;201:1157-1167.
[280] Honda K, Sakaguchi S, Nakajima C, et al. Selective contribution of IFN-alpha/beta signaling to the maturation of dendritic cells induced by double-stranded RNA or viral infection. Proceedings of the National Academy of Sciences of the United States of America 2003;100:10872-10877.
[281] Montoya M, Schiavoni G, Mattei F, et al. Type I interferons produced by dendritic cells promote their phenotypic and functional activation. Blood 2002;99:3263-3271.
[282] Kuchtey J, Chefalo PJ, Gray RC, et al. Enhancement of dendritic cell antigen cross- presentation by CpG DNA involves type I IFN and stabilization of class I MHC mRNA. J Immunol 2005; 175:2244-2251.
[283] Le Bon A, Etchart N, Rossmann C, et al. Cross-priming of CD8+ T cells stimulated by virus-induced type I interferon. Nature immunology 2003;4:1009-1015.
[284] Le Bon A, Schiavoni G, D'Agostino G, et al. Type i interferons potently enhance humoral immunity and can promote isotype switching by stimulating dendritic cells in vivo. Immunity 2001; 14:461-470.
[285] Gautier G, Humbert M, Deauvieau F, et al. A type I interferon autocrine-paracrine loop is involved in Toll-like receptor-induced interleukin-12p70 secretion by dendritic cells. The Journal of experimental medicine 2005;201:1435-1446.
[286] Pollara G, Handley ME, Kwan A, et al. Autocrine type I interferon amplifies dendritic cell responses to lipopolysaccharide via the nuclear factor-kappaB/p38 pathways. Scandinavian journal of immunology 2006;63:151 -154.
[287] Flores RR, Diggs KA, Tait LM, et al. IFN-gamma negatively regulates CpG-induced IL-10 in bone marrow-derived dendritic cells. J Immunol 2007;178:211-218.
[288] Heystek HC, den Drijver B, Kapsenberg ML, et al. Type I IFNs differentially modulate IL-12p70 production by human dendritic cells depending on the maturation status of the cells and counteract IFN-gamma-mediated signaling. Clinical immunology (Orlando, Fla 2003;107:170-177.
[289] Luft T, Luetjens P, Hochrein H, et al. IFN-alpha enhances CD40 ligand-mediated activation of immature monocyte-derived dendritic cells. International immunology 2002;14:367-380.
[290] McRae BL, Semnani RT, Hayes MP, et al. Type I IFNs inhibit human dendritic cell IL-12 production and Th1 cell development. J Immunol 1998; 160:4298-4304.
[291] Cousens LP, Orange JS, Su HC, et al. Interferon-alpha/beta inhibition of interleukin 12 and interferon-gamma production in vitro and endogenously during viral infection. Proceedings of the National Academy of Sciences of the United States of America 1997;94:634-639.
[292] Krug A, French AR, Barchet W, et al. TLR9-dependent recognition of MCMV by IPC and DC generates coordinated cytokine responses that activate antiviral NK cell function. Immunity 2004;21:107-119.
[293] Longman RS, Braun D, Pellegrini S, et al. Dendritic-cell maturation alters intracellular signaling networks, enabling differential effects of IFN-{alpha}/{beta} on antigen cross-presentation. Blood 2007; 109:1113-1122.
[294] Taniguchi T, Takaoka A. The interferon-alpha/beta system in antiviral responses: a multimodal machinery of gene regulation by the IRF family of transcription factors. Current opinion in immunology 2002;14:l 11-116.
[295] Tassiulas I, Hu X, Ho H, et al. Amplification of IFN-alpha-induced STAT1 activationand inflammatory function by Syk and ITAM-containing adaptors. Nature immunology 2004;5:l 181-1189.
[296] Byrnes AA, Ma X, Cuomo P, et al. Type I interferons and IL-12: convergence and cross-regulation among mediators of cellular immunity. European journal of immunology 2001 ;31:2026-2034.
[297] Sharif MN, Sosic D, Rothlin CV, et al. Twist mediates suppression of inflammation by type I IFNs and Axl. The Journal of experimental medicine 2006;203:1891-1901.
[298] Sauer I, Schaljo B, Vogl C, et al. Interferons limit inflammatory responses by induction of tristetraprolin. Blood 2006; 107:4790-4797.
[299] Ho HH, Ivashkiv LB. Role of STAT3 in type I interferon responses. Negative regulation of STAT1-dependent inflammatory gene activation. The Journal of biological chemistry 2006;281:14111-14118.
[300] Karaghiosoff M, Steinborn R, Kovarik P, et al. Central role for type I interferons and Tyk2 in lipopolysaccharide-induced endotoxin shock. Nature immunology 2003;4:471-477.
[301] Weighardt H, Kaiser-Moore S, Schlautkotter S, et al. Type I IFN modulates host defense and late hyperinflammation in septic peritonitis. J Immunol 2006;177:5623- 5630.
[302] Mahieu T, Park JM, Revets H, et al. The wild-derived inbred mouse strain SPRET/Ei is resistant to LPS and defective in IFN-beta production. Proceedings of the National Academy of Sciences of the United States of America 2006;103:2292-2297.
[303] Ronnblom L, Eloranta ML, Alm GV. The type I interferon system in systemic lupus erythematosus. Arthritis Rheum 2006;54:408-420.
[304] Banchereau J, Pascual V. Type I interferon in systemic lupus erythematosus and other autoimmune diseases. Immunity 2006;25:383-392.
[305] Decker T, Muller M, Stockinger S. The yin and yang of type I interferon activity in bacterial infection. Nature reviews 2005;5:675-687.
[306] Koga R, Hamano S, Kuwata H, et al. TLR-Dependent Induction of IFN-beta Mediates Host Defense against Trypanosoma cruzi. J Immunol 2006; 177:7059-7066.
[307] Zamvil SS, Steinman L. Diverse targets for intervention during inflammatory and neurodegenerative phases of multiple sclerosis. Neuron 2003;38:685-688.
[308] Teige I, Liu Y, Issazadeh-Navikas S. IFN-beta inhibits T cell activation capacity of central nervous system APCs. J Immunol 2006; 177:3542-3553.
[309] Tuohy VK, Yu M, Yin L, et al. Modulation of the IL-10/IL-12 cytokine circuit by interferon-beta inhibits the development of epitope spreading and disease progression in murine autoimmune encephalomyelitis. J Neuroimmunol 2000; 111:55-63.
[310] Floris S, Ruuls SR, Wierinckx A, et al. Interferon-beta directly influences monocyte infiltration into the central nervous system. J Neuroimmunol 2002; 127:69-79.
[311] Katakura K, Lee J, Rachmilewitz D, et al. Toll-like receptor 9-induced type I IFN protects mice from experimental colitis. The Journal of clinical investigation 2005 ;115:695-702.
[312] Geissmann F, Jung S, Littman DR. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 2003;19:71-82.
[313] Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nature reviews 2005;5:953-964.
[314] Bennouna S, Denkers EY. Microbial antigen triggers rapid mobilization of TNF-alpha to the surface of mouse neutrophils transforming them into inducers of high-level dendritic cell TNF-alpha production. J Immunol 2005; 174:4845-4851.
[315] Bliss SK, Butcher BA, Denkers EY. Rapid recruitment of neutrophils containing prestored IL-12 during microbial infection. J Immunol 2000; 165:4515-4521.
[316] Romani L, Mencacci A, Cenci E, et al. Neutrophil production of IL-12 and IL-10 in candidiasis and efficacy of IL-12 therapy in neutropenic mice. J Immunol 1997;158:5349-5356.
[317] Yi AK, Yoon JG, Yeo SJ, et al. Role of mitogen-activated protein kinases in CpG DNA-mediated IL-10 and IL-12 production: central role of extracellular signal- regulated kinase in the negative feedback loop of the CpG DNA-mediated Th1 response. J Immunol 2002;168:4711-4720.
[318] Lucas M, Zhang X, Prasanna V, et al. ERK activation following macrophage FcgammaR ligation leads to chromatin modifications at the IL-10 locus. J Immunol 2005; 175:469-477.
[319] Bliss SK, Zhang Y, Denkers EY. Murine neutrophil stimulation by Toxoplasma gondii antigen drives high level production of IFN-gamma-independent IL-12. J Immunol 1999;163:2081-2088.
[320] Chelvarajan RL, Collins SM, Doubinskaia IE, et al. Defective macrophage function in neonates and its impact on unresponsiveness of neonates to polysaccharide antigens. Journal of leukocyte biology 2004;75:982-994.
[321] Moore KW, de Waal Malefyt R, Coffman RL, et al. Interleukin-10 and the interleukin- 10 receptor. Annual review of immunology 2001;19:683-765.
[322] Mizoguchi A, Bhan AK. A case for regulatory B cells. J Immunol 2006; 176:705-710.
[323] Brightbill HD, Plevy SE, Modlin RL, et al. A prominent role for Sp1 during lipopolysaccharide-mediated induction of the IL-10 promoter in macrophages. J Immunol 2000; 164:1940-1951.
[324] Cao S, Liu J, Song L, et al. The protooncogene c-Maf is an essential transcription factor for IL-10 gene expression in macrophages. J Immunol 2005;174:3484-3492.
[325] Benkhart EM, Siedlar M, Wedel A, et al. Role of Stat3 in lipopolysaccharide-induced IL-10 gene expression. J Immunol 2000; 165:1612-1617.
[326] Cao S, Zhang X, Edwards JP, et al. NF-kappaB1 (p50) homodimers differentially regulate pro- and anti-inflammatory cytokines in macrophages. The Journal of biological chemistry 2006;281:26041-26050.
[327] Qian C, Jiang X, An H, et al. TLR agonists promote ERK-mediated preferential IL-10 production of regulatory dendritic cells (diffDCs), leading to NK-cell activation. Blood 2006;108:2307-2315.
[328] Yang Z, Mosser DM, Zhang X. Activation of the MAPK, ERK, following Leishmania amazonensis infection of macrophages. J Immunol 2007;178:1077-1085.
[329] Zhang X, Edwards JP, Mosser DM. Dynamic and transient remodeling of the macrophage IL-10 promoter during transcription. J Immunol 2006; 177:1282-1288.
[330] Teige I, Treschow A, Teige A, et al. IFN-beta gene deletion leads to augmented and chronic demyelinating experimental autoimmune encephalomyelitis. J Immunol 2003;170:4776-4784.
[331] Yarilina A, Dicarlo E, Ivashkiv LB. Suppression of the Effector Phase of Inflammatory Arthritis by Double-Stranded RNA Is Mediated by Type I IFNs. J Immunol 2007; 178:2204-2211.
[332] Bengtsson AA, Sturfelt G, Truedsson L, et al. Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not with antiretroviral antibodies. Lupus 2000;9:664-671.
[333] Bennett L, Palucka AK, Arce E, et al. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. The Journal of experimental medicine 2003;197:711-723.
[334] Santiago-Raber ML, Baccala R, Haraldsson KM, et al. Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice. The Journal of experimental medicine 2003; 197:777-788.
[335] Braun D, Geraldes P, Demengeot J. Type I Interferon controls the onset and severity of autoimmune manifestations in lpr mice. Journal of autoimmunity 2003;20:15-25.
[336] Jorgensen TN, Thurman J, Izui S, et al. Genetic susceptibility to PolyI:C-induced IFNalpha/beta-dependent accelerated disease in lupus-prone mice. Genes Immun 2006;7:555-567.
[337] Magnusson M, Zare F, Tarkowski A. Requirement of type I interferon signaling for arthritis triggered by double-stranded RNA. Arthritis and rheumatism 2006;54:148- 157.
[338] Vallin H, Perers A, Alm GV, et al. Anti-double-stranded DNA antibodies and immunostimulatory plasmid DNA in combination mimic the endogenous IFN-alpha inducer in systemic lupus erythematosus. J Immunol 1999; 163:6306-6313.
[339] Mancuso G, Midiri A, Biondo C, et al. Type I IFN Signaling Is Crucial for Host Resistance against Different Species of Pathogenic Bacteria. J Immunol 2007;178:3126-3133.
[1] Tsolis RM, Kingsley RA, Townsend SM, et al. Of mice, calves, and men. Comparison of the mouse typhoid model with other Salmonella infections. Advances in experimental medicine and biology 1999;473:261-274.
[2] Stocker BA. Aromatic-dependent salmonella as anti-bacterial vaccines and as presenters of heterologous antigens or of DNA encoding them. Journal of biotechnology 2000;83:45-50.
[3] Sirard JC, Niedergang F, Kraehenbuhl JP. Live attenuated Salmonella: a paradigm of mucosal vaccines. Immunological reviews 1999;171:5-26.
[4] Schoen C, Stritzker J, Goebel W, et al. Bacteria as DNA vaccine carriers for genetic immunization. Int J Med Microbiol 2004;294:319-335.
[5] Hess J, Gentschev I, Miko D, et al. Superior efficacy of secreted over somatic antigen display in recombinant Salmonella vaccine induced protection against listeriosis. Proceedings of the National Academy of Sciences of the United States of America 1996;93:1458-1463.
[6] Hess J, Dietrich G, Gentschev I, et al. Protection against murine listeriosis by an attenuated recombinant Salmonella typhimurium vaccine strain that secretes the naturally somatic antigen superoxide dismutase. Infection and immunity 1997;65:1286-1292.
[7] Grillot-Courvalin C, Goussard S, Courvalin P. Wild-type intracellular bacteria deliver DNA into mammalian cells. Cellular microbiology 2002;4:177-186.
[8] Garmory HS, Titball RW, Brown KA, et al. Construction and evaluation of a eukaryotic expression plasmid for stable delivery using attenuated Salmonella. Microbial pathogenesis 2003;34:115-119.
[9] Brumell JH, Grinstein S. Salmonella redirects phagosomal maturation. Current opinion in microbiology 2004;7:78-84.
[10] Garmory HS, Griffin KF, Leary SE, et al. The effect of recombinant plasmids on in vivo colonisation of Salmonella enterica serovar Typhimurium strains is not reflected by in vitro cellular invasion assays. Vaccine 2002;20:3239-3243.
[11] Dunstan SJ, Simmons CP, Strugnell RA. In vitro and in vivo stability of recombinant plasmids in a vaccine strain of Salmonella enterica var. Typhimurium. FEMS immunology and medical microbiology 2003;37:l 11-119.
[12] Boucrot E, Henry T, Borg JP, et al. The intracellular fate of Salmonella depends on the recruitment of kinesin. Science 2005;308:1174-1178.
[13] Beuzon CR, Meresse S, Unsworth KE, et al. Salmonella maintains the integrity of its intracellular vacuole through the action of SifA. The EMBO journal 2000;19:3235- 3249.
[14] Beuzon CR, Salcedo SP, Holden DW. Growth and killing of a Salmonella enterica serovar Typhimurium sifA mutant strain in the cytosol of different host cell lines. Microbiology (Reading, England) 2002;148:2705-2715.
[15] Wick MJ, Harding CV, Normark SJ, et al. Parameters that influence the efficiency ofprocessing antigenic epitopes expressed in Salmonella typhimurium. Infection and immunity 1994;62:4542-4548.
[16] Covone MG, Brocchi M, Palla E, et al. Levels of expression and immunogenicity of attenuated Salmonella enterica serovar typhimurium strains expressing Escherichia coli mutant heat-labile enterotoxin. Infection and immunity 1998;66:224-231.
[17] Galan JE, Nakayama K, Curtiss R, 3rd. Cloning and characterization of the asd gene of Salmonella typhimurium: use in stable maintenance of recombinant plasmids in Salmonella vaccine strains. Gene 1990;94:29-35.