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.
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