草鱼转化生长因子β1的免疫调节功能及其作用机制
|
摘要
TGF-β1属于TGF-β超家族，研究表明它在哺乳动物免疫系统中发挥了重要的调节作用，尤其在外周免疫系统中能诱导激活CD4阳性幼T细胞表达Foxp3，从而分化形成具有维持免疫耐受与抑制自免疫反应功能的调节性T（Treg）细胞亚群。
相对于哺乳动物中的深入研究，TGF-β1在包括硬骨鱼的低等脊椎动物免疫系统中的功能地位并不清楚。本论文以草鱼外周血白细胞和头肾白细胞为模型，发现TGF-β1对这两群细胞的活性，T/B细胞标志分子（CD4、CD8α/β和Igμ）和效应分子（TNF-α和IFN-γ）的表达分别产生了刺激和抑制两种调节作用。这种相反的调节功能可能与不同模型中的免疫细胞亚群的种类和状态相关。
进一步的研究证明，TGF-β1I型受体activin receptor-like kinase5（ALK5）参与了上述双向调节过程。尤其重要的是ALK5mRNA表达与蛋白水平被TGF-β1明显的下调，进而降低了ALK5阳性细胞在各细胞模型中的比例；这一发现被接下来的TGF-β1免疫中和实验所证实，提示一种基于受体层面的TGF-β1信号通路负调控机制的存在。有趣的是，TGF-β1的双向调节功能和降低受体表达作用均是通过短时的‘触发’方式来实现，而不需要长时间的刺激。这一现象可能与下调ALK5表达的机制来共同防止TGF-β1过度调控。
基于哺乳动物免疫系统中Foxp3作为TGF-β1免疫抑制功能重要载体的事实，我们在分离克隆草鱼转录因子Foxp3基因的基础上，发现TGF-β1在硬骨鱼白细胞中不仅明显上调Foxp3基因和蛋白表达水平，而且诱导头肾白细胞分化形成Foxp3阳性细胞亚群。研究证实这类细胞与哺乳动物Treg细胞具有相似的免疫抑制功能，具体表现为对激活白细胞活性的抑制以及下调该细胞中效应分子（TNF-α和IFN-γ）基因的表达。对这种现象的相关机制进一步研究证明草鱼Foxp3阳性细胞亚群是通过分泌TGF-β1与IL-10，以非细胞接触形式来发挥免疫抑制的作用。
该结果与哺乳动物诱导性Treg细胞的作用特征相符合。综上所述，本论文首先揭示了TGF-β1在鱼类免疫中的双向调节作用，以及其受体层面的自调控机制，其次阐明了硬骨鱼TGF-β1诱导产生Foxp3阳性细胞亚群的免疫抑制功能及其作用机制。研究结果从分子和细胞层面首次明确了硬骨鱼中“TGF-β1-Foxp3-类Treg细胞”调节机制，为鱼类免疫学增添了新内容。
TGF-β1belongs to the TGF-β1superfamily, and its pivotal regulatory roles inmammalian immune system have already been extensively characterized. Generally,TGF-β1promotes the expression of Foxp3in activated na ve CD4+cells, resulting inthe generation of the Foxp3+Treg subgroup, which acts as a potent immune suppressivemediator to maintain the immune tolerance and prevent autoimmunity.
However, the functional role of TGF-β1in the immune system of teleost is poorlyunderstood. In this study, we examined the immunoregulatory effects of TGF-β1ingrass carp peripheral blood leukocytes (PBL) and head kidney leukocytes (HKL). It isinteresting that TGF-β1consistently stimulated the cell viability and the mRNA levelsof pro-inflammatory cytokines (tnfα and ifnγ) and T/B cell markers [cd4-like (cd4l),cd8α, cd8β and igμ] in PBL, which contrasted with its inhibitory tone in HKL. It seemsthat the bidirectional function of TGF-β1in grass carp may correlate with the oppositestatus of the subsets in PBL and HKL.
Further studies showed that grass carp TGF-β1type I receptor, activin receptor-likekinase5(ALK5), was indispensable for the immunoregulatory effects of TGF-β1inPBL and HKL. Notably, TGF-β1persistently attenuated ALK5expression, whereasimmunoneutralization of endogenous grass carp TGF-β1could increase ALK5mRNAand protein levels. It is consistent with the observation that TGF-β1decreased thenumber of ALK5+leukocytes in PBL and HKL, revealing a negative regulation ofTGF-β1signaling at the receptor level. Moreover, transient treatment with TGF-β1for24h was sufficient to induce similar cellular responses compared with the continuoustreatment. This indicated a possible mechanism by which TGF-β1triggered thedown-regulation of ALK5mRNA and protein, leading to the desensitization of grasscarp leukocytes toward TGF-β1.
Considering the potential effect of TGF-β1on Foxp3expression and the crucialrole of Foxp3expression in Treg activity in mammals, grass carp foxp3(gcfoxp3) genewas cloned and identified in this study. As expected, TGF-β1was effective in up-regulating gcFoxp3mRNA and protein levels in HKL. Meanwhile, TGF-β1inducedthe generation of grass carp Foxp3+cells. Similar to mammalian Treg, these cellsdisplayed immune suppressive activities in co-culture system in which Foxp3+cellsinduced by TGF-β1down-regulated the cell viability and the expression of effectormolecules (tnfα and ifnγ) of the responder cells stimulated by PHA. A possibleexplanation for the suppressive functions of these Foxp3+cells could be due to thesecretion of cytokines (TGF-β1and IL-10) via a non-cell contact mechanism.
Accordingly, our data revealed a dual role of TGF-β1in teleost immunity in whichit can serve as a positive or negative control device and provided additional mechanisticinsights as to how TGF-β1controls its signaling in vertebrate leukocytes. Furthermore,we demonstrated the regulatory mechanism of ‘TGF-β1-Foxp3-Treg-like cells’ axis inteleost.
相对于哺乳动物中的深入研究，TGF-β1在包括硬骨鱼的低等脊椎动物免疫系统中的功能地位并不清楚。本论文以草鱼外周血白细胞和头肾白细胞为模型，发现TGF-β1对这两群细胞的活性，T/B细胞标志分子（CD4、CD8α/β和Igμ）和效应分子（TNF-α和IFN-γ）的表达分别产生了刺激和抑制两种调节作用。这种相反的调节功能可能与不同模型中的免疫细胞亚群的种类和状态相关。
进一步的研究证明，TGF-β1I型受体activin receptor-like kinase5（ALK5）参与了上述双向调节过程。尤其重要的是ALK5mRNA表达与蛋白水平被TGF-β1明显的下调，进而降低了ALK5阳性细胞在各细胞模型中的比例；这一发现被接下来的TGF-β1免疫中和实验所证实，提示一种基于受体层面的TGF-β1信号通路负调控机制的存在。有趣的是，TGF-β1的双向调节功能和降低受体表达作用均是通过短时的‘触发’方式来实现，而不需要长时间的刺激。这一现象可能与下调ALK5表达的机制来共同防止TGF-β1过度调控。
基于哺乳动物免疫系统中Foxp3作为TGF-β1免疫抑制功能重要载体的事实，我们在分离克隆草鱼转录因子Foxp3基因的基础上，发现TGF-β1在硬骨鱼白细胞中不仅明显上调Foxp3基因和蛋白表达水平，而且诱导头肾白细胞分化形成Foxp3阳性细胞亚群。研究证实这类细胞与哺乳动物Treg细胞具有相似的免疫抑制功能，具体表现为对激活白细胞活性的抑制以及下调该细胞中效应分子（TNF-α和IFN-γ）基因的表达。对这种现象的相关机制进一步研究证明草鱼Foxp3阳性细胞亚群是通过分泌TGF-β1与IL-10，以非细胞接触形式来发挥免疫抑制的作用。
该结果与哺乳动物诱导性Treg细胞的作用特征相符合。综上所述，本论文首先揭示了TGF-β1在鱼类免疫中的双向调节作用，以及其受体层面的自调控机制，其次阐明了硬骨鱼TGF-β1诱导产生Foxp3阳性细胞亚群的免疫抑制功能及其作用机制。研究结果从分子和细胞层面首次明确了硬骨鱼中“TGF-β1-Foxp3-类Treg细胞”调节机制，为鱼类免疫学增添了新内容。
TGF-β1belongs to the TGF-β1superfamily, and its pivotal regulatory roles inmammalian immune system have already been extensively characterized. Generally,TGF-β1promotes the expression of Foxp3in activated na ve CD4+cells, resulting inthe generation of the Foxp3+Treg subgroup, which acts as a potent immune suppressivemediator to maintain the immune tolerance and prevent autoimmunity.
However, the functional role of TGF-β1in the immune system of teleost is poorlyunderstood. In this study, we examined the immunoregulatory effects of TGF-β1ingrass carp peripheral blood leukocytes (PBL) and head kidney leukocytes (HKL). It isinteresting that TGF-β1consistently stimulated the cell viability and the mRNA levelsof pro-inflammatory cytokines (tnfα and ifnγ) and T/B cell markers [cd4-like (cd4l),cd8α, cd8β and igμ] in PBL, which contrasted with its inhibitory tone in HKL. It seemsthat the bidirectional function of TGF-β1in grass carp may correlate with the oppositestatus of the subsets in PBL and HKL.
Further studies showed that grass carp TGF-β1type I receptor, activin receptor-likekinase5(ALK5), was indispensable for the immunoregulatory effects of TGF-β1inPBL and HKL. Notably, TGF-β1persistently attenuated ALK5expression, whereasimmunoneutralization of endogenous grass carp TGF-β1could increase ALK5mRNAand protein levels. It is consistent with the observation that TGF-β1decreased thenumber of ALK5+leukocytes in PBL and HKL, revealing a negative regulation ofTGF-β1signaling at the receptor level. Moreover, transient treatment with TGF-β1for24h was sufficient to induce similar cellular responses compared with the continuoustreatment. This indicated a possible mechanism by which TGF-β1triggered thedown-regulation of ALK5mRNA and protein, leading to the desensitization of grasscarp leukocytes toward TGF-β1.
Considering the potential effect of TGF-β1on Foxp3expression and the crucialrole of Foxp3expression in Treg activity in mammals, grass carp foxp3(gcfoxp3) genewas cloned and identified in this study. As expected, TGF-β1was effective in up-regulating gcFoxp3mRNA and protein levels in HKL. Meanwhile, TGF-β1inducedthe generation of grass carp Foxp3+cells. Similar to mammalian Treg, these cellsdisplayed immune suppressive activities in co-culture system in which Foxp3+cellsinduced by TGF-β1down-regulated the cell viability and the expression of effectormolecules (tnfα and ifnγ) of the responder cells stimulated by PHA. A possibleexplanation for the suppressive functions of these Foxp3+cells could be due to thesecretion of cytokines (TGF-β1and IL-10) via a non-cell contact mechanism.
Accordingly, our data revealed a dual role of TGF-β1in teleost immunity in whichit can serve as a positive or negative control device and provided additional mechanisticinsights as to how TGF-β1controls its signaling in vertebrate leukocytes. Furthermore,we demonstrated the regulatory mechanism of ‘TGF-β1-Foxp3-Treg-like cells’ axis inteleost.
引文
[1] Chang H., Brown C. W., Matzuk M. M. Genetic analysis of the mammalian transforminggrowth factor-beta superfamily. Endocr Rev.2002,23(6): p.787-823.
[2] Govinden R., Bhoola K. D. Genealogy, expression, and cellular function of transforminggrowth factor-beta. Pharmacol Ther.2003,98(2): p.257-65.
[3] Gorelik L., Flavell R. A. Abrogation of TGFbeta signaling in T cells leads to spontaneous Tcell differentiation and autoimmune disease. Immunity.2000,12(2): p.171-81.
[4] Li M. O., Wan Y. Y., Sanjabi S., et al. Transforming growth factor-beta regulation ofimmune responses. Annu Rev Immunol.2006,24: p.99-146.
[5] Reiner S. L. Development in motion: helper T cells at work. Cell.2007,129(1): p.33-6.
[6] Gorelik L., Constant S., Flavell R. A. Mechanism of transforming growth factorbeta-induced inhibition of T helper type1differentiation. J Exp Med.2002,195(11): p.1499-505.
[7] Cerwenka A., Swain S. L. TGF-beta1: immunosuppressant and viability factor for Tlymphocytes. Microbes Infect.1999,1(15): p.1291-6.
[8] Kobayashi S., Yoshida K., Ward J. M., et al. Beta2-microglobulin-deficient backgroundameliorates lethal phenotype of the TGF-beta1null mouse. J Immunol.1999,163(7): p.4013-9.
[9] Horwitz D. A., Zheng S. G., Gray J. D. The role of the combination of IL-2and TGF-beta orIL-10in the generation and function of CD4+CD25+and CD8+regulatory T cell subsets. JLeukoc Biol.2003,74(4): p.471-8.
[10] Chen W., Jin W., Hardegen N., et al. Conversion of peripheral CD4+CD25-naive T cells toCD4+CD25+regulatory T cells by TGF-beta induction of transcription factor Foxp3. J ExpMed.2003,198(12): p.1875-86.
[11] Fantini M. C., Becker C., Monteleone G., et al. Cutting edge: TGF-beta induces a regulatoryphenotype in CD4+CD25-T cells through Foxp3induction and down-regulation of Smad7.J Immunol.2004,172(9): p.5149-53.
[12] Zheng S. G., Wang J. H., Gray J. D., et al. Natural and induced CD4+CD25+cells educateCD4+CD25-cells to develop suppressive activity: the role of IL-2, TGF-beta, and IL-10. JImmunol.2004,172(9): p.5213-21.
[13] Gershon R. K. A disquisition on suppressor T cells. Transplant Rev.1975,26: p.170-85.
[14] Cazac B. B., Roes J. TGF-beta receptor controls B cell responsiveness and induction of IgAin vivo. Immunity.2000,13(4): p.443-51.
[15] Stavnezer J. Regulation of antibody production and class switching by TGF-beta. JImmunol.1995,155(4): p.1647-51.
[16] Lebman D. A., Edmiston J. S. The role of TGF-beta in growth, differentiation, andmaturation of B lymphocytes. Microbes Infect.1999,1(15): p.1297-304.
[17] Rook A. H., Kehrl J. H., Wakefield L. M., et al. Effects of transforming growth factor betaon the functions of natural killer cells: depressed cytolytic activity and blunting of interferonresponsiveness. J Immunol.1986,136(10): p.3916-20.
[18] Bellone G., Aste-Amezaga M., Trinchieri G., et al. Regulation of NK cell functions byTGF-beta1. J Immunol.1995,155(3): p.1066-73.
[19] Hunter C. A., Bermudez L., Beernink H., et al. Transforming growth factor-beta inhibitsinterleukin-12-induced production of interferon-gamma by natural killer cells: a role fortransforming growth factor-beta in the regulation of T cell-independent resistance toToxoplasma gondii. Eur J Immunol.1995,25(4): p.994-1000.
[20] Steinman R. M., Hawiger D., Nussenzweig M. C. Tolerogenic dendritic cells. Annu RevImmunol.2003,21: p.685-711.
[21] Strobl H., Knapp W. TGF-beta1regulation of dendritic cells. Microbes Infect.1999,1(15):p.1283-90.
[22] Ashcroft G. S. Bidirectional regulation of macrophage function by TGF-beta. MicrobesInfect.1999,1(15): p.1275-82.
[23] Gruber B. L., Marchese M. J., Kew R. R. Transforming growth factor-beta1mediates mastcell chemotaxis. J Immunol.1994,152(12): p.5860-7.
[24] Olsson N., Piek E., ten Dijke P., et al. Human mast cell migration in response to members ofthe transforming growth factor-beta family. J Leukoc Biol.2000,67(3): p.350-6.
[25] Klion A. D., Nutman T. B. The role of eosinophils in host defense against helminth parasites.J Allergy Clin Immunol.2004,113(1): p.30-7.
[26] Munitz A., Levi-Schaffer F. Eosinophils:'new' roles for 'old' cells. Allergy.2004,59(3): p.268-75.
[27] Litman G. W., Cooper M. D. Why study the evolution of immunity? Nat Immunol.2007,8(6): p.547-8.
[28] Haddad G., Hanington P. C., Wilson E. C., et al. Molecular and functional characterizationof goldfish (Carassius auratus L.) transforming growth factor beta. Dev Comp Immunol.2008,32(6): p.654-63.
[29] Grayfer L., Belosevic M. Molecular characterization of tumor necrosis factor receptors1and2of the goldfish (Carassius aurutus L.). Mol Immunol.2009,46(11-12): p.2190-9.
[30] Cai Z., Gao C., Li L., et al. Bipolar properties of red seabream (Pagrus major) transforminggrowth factor-beta in induction of the leucocytes migration. Fish Shellfish Immunol.2010,28(4): p.695-700.
[31] Ohtsuka K., Gray J. D., Stimmler M. M., et al. Decreased production of TGF-beta bylymphocytes from patients with systemic lupus erythematosus. J Immunol.1998,160(5): p.2539-45.
[32] Dang H., Geiser A. G., Letterio J. J., et al. SLE-like autoantibodies and Sjogren'ssyndrome-like lymphoproliferation in TGF-beta knockout mice. J Immunol.1995,155(6): p.3205-12.
[33] Yaswen L., Kulkarni A. B., Fredrickson T., et al. Autoimmune manifestations in thetransforming growth factor-beta1knockout mouse. Blood.1996,87(4): p.1439-45.
[34] Holmdahl R., Bockermann R., Backlund J., et al. The molecular pathogenesis ofcollagen-induced arthritis in mice--a model for rheumatoid arthritis. Ageing Res Rev.2002,1(1): p.135-47.
[35] Thorbecke G. J., Shah R., Leu C. H., et al. Involvement of endogenous tumor necrosis factoralpha and transforming growth factor beta during induction of collagen type II arthritis inmice. Proc Natl Acad Sci U S A.1992,89(16): p.7375-9.
[36] Grewal I. S., Grewal K. D., Wong F. S., et al. Expression of transgene encoded TGF-beta inislets prevents autoimmune diabetes in NOD mice by a local mechanism. J Autoimmun.2002,19(1-2): p.9-22.
[37] Peng Y., Laouar Y., Li M. O., et al. TGF-beta regulates in vivo expansion ofFoxp3-expressing CD4+CD25+regulatory T cells responsible for protection againstdiabetes. Proc Natl Acad Sci U S A.2004,101(13): p.4572-7.
[38] Friese M. A., Wischhusen J., Wick W., et al. RNA interference targeting transforminggrowth factor-beta enhances NKG2D-mediated antiglioma immune response, inhibitsglioma cell migration and invasiveness, and abrogates tumorigenicity in vivo. Cancer Res.2004,64(20): p.7596-603.
[39] Stander M., Naumann U., Dumitrescu L., et al. Decorin gene transfer-mediated suppressionof TGF-beta synthesis abrogates experimental malignant glioma growth in vivo. Gene Ther.1998,5(9): p.1187-94.
[40] Chang H. L., Gillett N., Figari I., et al. Increased transforming growth factor beta expressioninhibits cell proliferation in vitro, yet increases tumorigenicity and tumor growth of Meth Asarcoma cells. Cancer Res.1993,53(18): p.4391-8.
[41] Fakhrai H., Dorigo O., Shawler D. L., et al. Eradication of established intracranial ratgliomas by transforming growth factor beta antisense gene therapy. Proc Natl Acad Sci U SA.1996,93(7): p.2909-14.
[42] Sutmuller R. P., van Duivenvoorde L. M., van Elsas A., et al. Synergism of cytotoxic Tlymphocyte-associated antigen4blockade and depletion of CD25(+) regulatory T cells inantitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic Tlymphocyte responses. J Exp Med.2001,194(6): p.823-32.
[43] Shimizu J., Yamazaki S., Sakaguchi S. Induction of tumor immunity by removingCD25+CD4+T cells: a common basis between tumor immunity and autoimmunity. JImmunol.1999,163(10): p.5211-8.
[44] Onizuka S., Tawara I., Shimizu J., et al. Tumor rejection by in vivo administration ofanti-CD25(interleukin-2receptor alpha) monoclonal antibody. Cancer Res.1999,59(13): p.3128-33.
[45] Scherf W., Burdach S., Hansen G. Reduced expression of transforming growth factor beta1exacerbates pathology in an experimental asthma model. Eur J Immunol.2005,35(1): p.198-206.
[46] Mallat Z., Gojova A., Marchiol-Fournigault C., et al. Inhibition of transforming growthfactor-beta signaling accelerates atherosclerosis and induces an unstable plaque phenotypein mice. Circ Res.2001,89(10): p.930-4.
[47] Lutgens E., Gijbels M., Smook M., et al. Transforming growth factor-beta mediates balancebetween inflammation and fibrosis during plaque progression. Arterioscler Thromb VascBiol.2002,22(6): p.975-82.
[48] Hansen G., McIntire J. J., Yeung V. P., et al. T. CD4(+) T helper cells engineered to producelatent TGF-beta1reverse allergen-induced airway hyperreactivity and inflammation. J ClinInvest.2000,105(1): p.61-70.
[49] Gorelik L., Fields P. E., Flavell R. A. Cutting edge: TGF-beta inhibits Th type2development through inhibition of GATA-3expression. J Immunol.2000,165(9): p.4773-7.
[50] Tafalla C., Coll J., Secombes C. J. Expression of genes related to the early immune responsein rainbow trout (Oncorhynchus mykiss) after viral haemorrhagic septicemia virus (VHSV)infection. Dev Comp Immunol.2005,29(7): p.615-26.
[51] Bridle A. R., Morrison R. N., Nowak B. F. The expression of immune-regulatory genes inrainbow trout, Oncorhynchus mykiss, during amoebic gill disease (AGD). Fish ShellfishImmunol.2006,20(3): p.346-64.
[52] Mulder I. E., Wadsworth S.,Secombes C. J. Cytokine expression in the intestine of rainbowtrout (Oncorhynchus mykiss) during infection with Aeromonas salmonicida. Fish ShellfishImmunol.2007,23(4): p.747-59.
[53] Scapigliati G., Buonocore F., Randelli E., et al. Cellular and molecular immune responses ofthe sea bass (Dicentrarchus labrax) experimentally infected with betanodavirus. FishShellfish Immunol.2010,28(2): p.303-11.
[54] Eder K. J., Clifford M. A., Hedrick R. P., et al. Expression of immune-regulatory genes injuvenile Chinook salmon following exposure to pesticides and infectious hematopoieticnecrosis virus (IHNV). Fish Shellfish Immunol.2008,25(5): p.508-16.
[55] Skugor S., Glover K. A., Nilsen F., et al. Local and systemic gene expression responses ofAtlantic salmon (Salmo salar L.) to infection with the salmon louse (Lepeophtheirussalmonis). BMC Genomics.2008,9: p.498.
[56] Robertson L. S., Ottinger C. A., Burdick S. M., et al. Development of a quantitative assay tomeasure expression of transforming growth factor beta (TGF-beta) in Lost River sucker(Deltistes luxatus) and shortnose sucker (Chasmistes brevirostris) and evaluation ofpotential pitfalls in use with field-collected samples. Fish Shellfish Immunol.2012,32(5): p.890-8
[57] Huminiecki L., Goldovsky L., Freilich S., et al. Emergence, development and diversificationof the TGF-beta signalling pathway within the animal kingdom. BMC Evol Biol.2009,9: p.28.
[58] Annes J. P., Munger J. S.,Rifkin D. B. Making sense of latent TGFbeta activation. J Cell Sci.2003,116(Pt2): p.217-24.
[59] Crawford S. E., Stellmach V., Murphy-Ullrich J. E., et al. Thrombospondin-1is a majoractivator of TGF-beta1in vivo. Cell.1998,93(7): p.1159-70.
[60] Yehualaeshet T., O'Connor R., Green-Johnson J., et al. Activation of rat alveolarmacrophage-derived latent transforming growth factor beta-1by plasmin requiresinteraction with thrombospondin-1and its cell surface receptor, CD36. Am J Pathol.1999,155(3): p.841-51.
[61] Annes J. P., Chen Y., Munger J. S., et al. Integrin alphaVbeta6-mediated activation of latentTGF-beta requires the latent TGF-beta binding protein-1. J Cell Biol.2004,165(5): p.723-34.
[62] Munger J. S., Harpel J. G., Giancotti F. G., et al. Interactions between growth factors andintegrins: latent forms of transforming growth factor-beta are ligands for the integrinalphavbeta1. Mol Biol Cell.1998,9(9): p.2627-38.
[63] Munger J. S., Harpel J. G., Gleizes P. E., et al. Latent transforming growth factor-beta:structural features and mechanisms of activation. Kidney Int.1997,51(5): p.1376-82.
[64] Massague J. TGF-beta signal transduction. Annu Rev Biochem.1998,67: p.753-91.
[65] ten Dijke P., Hill C. S. New insights into TGF-beta-Smad signalling. Trends Biochem Sci.2004,29(5): p.265-73.
[66] Huse M., Muir T. W., Xu L., et al. The TGF beta receptor activation process: an inhibitor-tosubstrate-binding switch. Mol Cell.2001,8(3): p.671-82.
[67] Shi Y., Massague J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus.Cell.2003,113(6): p.685-700.
[68] Engel M. E., McDonnell M. A., Law B. K., et al. Interdependent SMAD and JNK signalingin transforming growth factor-beta-mediated transcription. J Biol Chem.1999,274(52): p.37413-20.
[69] Yu L., Hebert M. C., Zhang Y. E. TGF-beta receptor-activated p38MAP kinase mediatesSmad-independent TGF-beta responses. Embo J.2002,21(14): p.3749-59.
[70] Kohli G., Hu S., Clelland E., et al. Cloning of transforming growth factor-beta1(TGF-beta1) and its type II receptor from zebrafish ovary and role of TGF-beta1in oocyte maturation.Endocrinology.2003,144(5): p.1931-41.
[71] Wan Y. Y., Flavell R. A. TGF-beta and regulatory T cell in immunity and autoimmunity. JClin Immunol.2008,28(6): p.647-59.
[72] Wan Y. Y., Flavell R. A. Identifying Foxp3-expressing suppressor T cells with a bicistronicreporter. Proc Natl Acad Sci U S A.2005,102(14): p.5126-31.
[73] Marie J. C., Letterio J. J., Gavin M., et al. TGF-beta1maintains suppressor function andFoxp3expression in CD4+CD25+regulatory T cells. J Exp Med.2005,201(7): p.1061-7.
[74] Mamura M., Lee W., Sullivan T. J., et al. CD28disruption exacerbates inflammation inTgf-beta1-/-mice: in vivo suppression by CD4+CD25+regulatory T cells independent ofautocrine TGF-beta1. Blood.2004,103(12): p.4594-601.
[75] Fontenot J. D., Gavin M. A., Rudensky A. Y. Foxp3programs the development and functionof CD4+CD25+regulatory T cells. Nat Immunol.2003,4(4): p.330-6.
[76] Hori S., Nomura T., Sakaguchi S. Control of regulatory T cell development by thetranscription factor Foxp3. Science.2003,299(5609): p.1057-61.
[77] Sakaguchi S., Sakaguchi N., Asano M., et al. Immunologic self-tolerance maintained byactivated T cells expressing IL-2receptor alpha-chains (CD25). Breakdown of a singlemechanism of self-tolerance causes various autoimmune diseases. J Immunol.1995,155(3):p.1151-64.
[78] Khattri R., Cox T., Yasayko S. A.,Ramsdell F. An essential role for Scurfin in CD4+CD25+T regulatory cells. Nat Immunol.2003,4(4): p.337-42.
[79] Ochs H. D., Ziegler S. F., Torgerson T. R. FOXP3acts as a rheostat of the immune response.Immunol Rev.2005,203: p.156-64.
[80] Ziegler S. F. FOXP3: of mice and men. Annu Rev Immunol.2006,24: p.209-26.
[81] Bennett C. L., Christie J., Ramsdell F., et al. The immune dysregulation,polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations ofFOXP3. Nat Genet.2001,27(1): p.20-1.
[82] Chatila T. A., Blaeser F., Ho N., et al. M. JM2, encoding a fork head-related protein, ismutated in X-linked autoimmunity-allergic disregulation syndrome. J Clin Invest.2000,106(12): p. R75-81.
[83] Sakaguchi S., Miyara M., Costantino C. M., et al. FOXP3+regulatory T cells in the humanimmune system. Nat Rev Immunol.10(7): p.490-500.
[84] Yagi H., Nomura T., Nakamura K., et al. Crucial role of FOXP3in the development andfunction of human CD25+CD4+regulatory T cells. Int Immunol.2004,16(11): p.1643-56.
[85] Wan Y. Y., Flavell R. A. Regulatory T-cell functions are subverted and converted owing toattenuated Foxp3expression. Nature.2007,445(7129): p.766-70.
[86] Mitra S., Alnabulsi A., Secombes C. J., et al. Identification and characterization of thetranscription factors involved in T-cell development, t-bet, stat6and foxp3, within thezebrafish, Danio rerio. Febs J.2010,277(1): p.128-47.
[87] Quintana F. J., Iglesias A. H., Farez M. F., et al. Adaptive autoimmunity and Foxp3-basedimmunoregulation in zebrafish. PLoS One.2010,5(3): p. e9478.
[88] Wang T., Monte M. M., Huang W., et al. Identification of two FoxP3genes in rainbow trout(Oncorhynchus mykiss) with differential induction patterns. Mol Immunol.2010,47(16): p.2563-74.
[89] Zhang Z., Chi H., Niu C., et al. Molecular cloning and characterization of Foxp3in Atlanticsalmon (Salmo salar). Fish Shellfish Immunol.201130(3): p.902-9.
[90] Kaestner K. H., Knochel W., Martinez D. E. Unified nomenclature for the wingedhelix/forkhead transcription factors. Genes Dev.2000,14(2): p.142-6.
[91] Kaufmann E., Knochel W. Five years on the wings of fork head. Mech Dev.1996,57(1): p.3-20.
[92] Schubert L. A., Jeffery E., Zhang Y., et al. Scurfin (FOXP3) acts as a repressor oftranscription and regulates T cell activation. J Biol Chem.2001,276(40): p.37672-9.
[93] Kasprowicz D. J., Smallwood P. S., Tyznik A. J., et al. Scurfin (FoxP3) controlsT-dependent immune responses in vivo through regulation of CD4+T cell effector function.J Immunol.2003,171(3): p.1216-23.
[94] Bettelli E., Dastrange M., Oukka M. Foxp3interacts with nuclear factor of activated T cellsand NF-kappa B to repress cytokine gene expression and effector functions of T helper cells.Proc Natl Acad Sci U S A.2005,102(14): p.5138-43.
[95] Blobe G. C., Schiemann W. P., Lodish H. F. Role of transforming growth factor beta inhuman disease. N Engl J Med.2000,342(18): p.1350-8.
[96] Li M. O., Flavell R. A. TGF-beta: a master of all T cell trades. Cell.2008,134(3): p.392-404.
[97] Saxena V., Lienesch D. W., Zhou M., et al. Dual roles of immunoregulatory cytokineTGF-beta in the pathogenesis of autoimmunity-mediated organ damage. J Immunol.2008,180(3): p.1903-12.
[98] Zhang L., Yi H., Xia X. P., et al. Transforming growth factor-beta: an important role inCD4+CD25+regulatory T cells and immune tolerance. Autoimmunity.2006,39(4): p.269-76.
[99] Letterio J. J., Roberts A. B. Regulation of immune responses by TGF-beta. Annu RevImmunol.1998,16: p.137-61.
[100] Wahl S. M. Transforming growth factor beta: the good, the bad, and the ugly. J Exp Med.1994,180(5): p.1587-90.
[101] Li B., Samanta A., Song X., et al. FOXP3ensembles in T-cell regulation. Immunol Rev.2006,212: p.99-113.
[102] Wan Y. Y., Flavell R. A.'Yin-Yang' functions of transforming growth factor-beta and Tregulatory cells in immune regulation. Immunol Rev.2007,220: p.199-213.
[103] Laouar Y., Sutterwala F. S., Gorelik L., et al. Transforming growth factor-beta controls Thelper type1cell development through regulation of natural killer cell interferon-gamma.Nat Immunol.2005,6(6): p.600-7.
[104] Kadowaki T., Yasui Y., Takahashi Y., et al. Comparative immunological analysis of innateimmunity activation after oral administration of wheat fermented extract to teleost fish.Anticancer Res.2009,29(11): p.4871-7.
[105] Sepulcre M. P., Pelegrin P., Mulero V., et al. Characterisation of gilthead seabreamacidophilic granulocytes by a monoclonal antibody unequivocally points to theirinvolvement in fish phagocytic response. Cell Tissue Res.2002,308(1): p.97-102.
[106] Pettersen E. F., Bjerknes R.,Wergeland H. I. Studies of Atlantic salmon (Salmo salar L.)blood, spleen and head kidney leucocytes using specific monoclonal antibodies,immunohistochemistry and flow cytometry. Fish Shellfish Immunol.2000,10(8): p.695-710.
[107] Boschi I., Randelli E., Buonocore F., et al. Transcription of T cell-related genes in teleostfish, and the European sea bass (Dicentrarchus labrax) as a model. Fish Shellfish Immunol.2011,31(5): p.655-62.
[108] Zwollo P., Cole S., Bromage E., et al. B cell heterogeneity in the teleost kidney: evidencefor a maturation gradient from anterior to posterior kidney. J Immunol.2005,174(11): p.6608-16.
[109] Rodrigues P. N., Hermsen T. T., Rombout J. H., et al. Detection of MHC class II transcriptsin lymphoid tissues of the common carp (Cyprinus carpio L.). Dev Comp Immunol.1995,19(6): p.483-96.
[110] Kemenade B., Groeneveld A., Rens B., et al. Characterization of Macrophages andNeutrophilic Granulocytes from the Pronephros of Carp (Cyprinus Carpio). J Exp Biol.1994,187(1): p.143-58.
[111] Tafalla C., Aranguren R., Secombes C. J., et al. Molecular characterisation of sea bream(Sparus aurata) transforming growth factor beta1. Fish Shellfish Immunol.2003,14(5): p.405-21.
[112] Grayfer L., Hodgkinson J. W., Hitchen S. J., et al. Characterization and functional analysisof goldfish (Carassius auratus L.) interleukin-10. Mol Immunol.2011,48(4): p.563-71.
[113] Grayfer L., Walsh J. G., Belosevic M. Characterization and functional analysis of goldfish(Carassius auratus L.) tumor necrosis factor-alpha. Dev Comp Immunol.2008,32(5): p.532-43.
[114] Grayfer L., Belosevic M. Molecular characterization, expression and functional analysis ofgoldfish (Carassius aurutus L.) interferon gamma. Dev Comp Immunol.2009,33(2): p.235-46.
[115] Zou J., Peddie S., Scapigliati G., et al. Functional characterisation of the recombinant tumornecrosis factors in rainbow trout, Oncorhynchus mykiss. Dev Comp Immunol.2003,27(9):p.813-22.
[116] Saeij J. P., Stet R. J., de Vries B. J., et al. Molecular and functional characterization of carpTNF: a link between TNF polymorphism and trypanotolerance? Dev Comp Immunol.2003,27(1): p.29-41.
[117] Lopez-Munoz A., Roca F. J., Meseguer J., et al. New insights into the evolution of IFNs:zebrafish group II IFNs induce a rapid and transient expression of IFN-dependent genes anddisplay powerful antiviral activities. J Immunol.2009,182(6): p.3440-9.
[118] Arts J. A., Tijhaar E. J., Chadzinska M., et al. Functional analysis of carp interferon-gamma:evolutionary conservation of classical phagocyte activation. Fish Shellfish Immunol.2010,29(5): p.793-802.
[119] Stolte E. H., Savelkoul H. F., Wiegertjes G., et al. Differential expression of twointerferon-gamma genes in common carp (Cyprinus carpio L.). Dev Comp Immunol.2008,32(12): p.1467-81.
[120] Dijkstra J. M., Somamoto T., Moore L., et al. Identification and characterization of a secondCD4-like gene in teleost fish. Mol Immunol.2006,43(5): p.410-9.
[121] Sun X. F., Shang N., Hu W., et al. Molecular cloning and characterization of carp (Cyprinuscarpio L.) CD8beta and CD4-like genes. Fish Shellfish Immunol.2007,23(6): p.1242-55.
[122] Fischer U., Utke K., Ototake M., et al. Adaptive cell-mediated cytotoxicity againstallogeneic targets by CD8-positive lymphocytes of rainbow trout (Oncorhynchus mykiss).Dev Comp Immunol.2003,27(4): p.323-37.
[123] Hetland D. L., Jorgensen S. M., Skjodt K., et al. In situ localisation of majorhistocompatibility complex class I and class II and CD8positive cells in infectious salmonanaemia virus (ISAV)-infected Atlantic salmon. Fish Shellfish Immunol.2010,28(1): p.30-9.
[124] Picchietti S., Guerra L., Buonocore F., et al. Lymphocyte differentiation in sea bass thymus:CD4and CD8-alpha gene expression studies. Fish Shellfish Immunol.2009,27(1): p.50-6.
[125] Xiao F. S., Wang Y. P., Yan W., et al. Ig heavy chain genes and their locus in grass carpCtenopharyngodon idella. Fish Shellfish Immunol.2010,29(4): p.594-9.
[126] Ronneseth A., Wergeland H. I., Pettersen E. F. Neutrophils and B-cells in Atlantic cod(Gadus morhua L.). Fish Shellfish Immunol.2007,23(3): p.493-503.
[127] Inman G. J., Nicolas F. J., Hill C. S. Nucleocytoplasmic shuttling of Smads2,3, and4permits sensing of TGF-beta receptor activity. Mol Cell.2002,10(2): p.283-94.
[128] Liu Y., Zhang P., Li J., et al. A critical function for TGF-beta signaling in the developmentof natural CD4+CD25+Foxp3+regulatory T cells. Nat Immunol.2008,9(6): p.632-40.
[129] Markell L. M., Masiuk K. E., Blazanin N., et al. Pharmacologic inhibition of ALK5causesselective induction of terminal differentiation in mouse keratinocytes expressing oncogenicHRAS. Mol Cancer Res.2011,9(6): p.746-56.
[130] Mallet C., Vittet D., Feige J. J., et al. TGFbeta1induces vasculogenesis and inhibitsangiogenic sprouting in an embryonic stem cell differentiation model: respectivecontribution of ALK1and ALK5. Stem Cells.2006,24(11): p.2420-7.
[131] Miyazono K. TGF-beta/SMAD signaling and its involvement in tumor progression. BiolPharm Bull.2000,23(10): p.1125-30.
[132] Miyazono K., ten Dijke P., Heldin C. H. TGF-beta signaling by Smad proteins. AdvImmunol.2000,75: p.115-57.
[133] Ebisawa T., Fukuchi M., Murakami G., et al. Smurf1interacts with transforming growthfactor-beta type I receptor through Smad7and induces receptor degradation. J Biol Chem.2001,276(16): p.12477-80.
[134] Mitchell H., Choudhury A., Pagano R. E., et al. Ligand-dependent and-independenttransforming growth factor-beta receptor recycling regulated by clathrin-mediatedendocytosis and Rab11. Mol Biol Cell.2004,15(9): p.4166-78.
[135] de Caestecker M. P., Piek E., Roberts A. B. Role of transforming growth factor-betasignaling in cancer. J Natl Cancer Inst.2000,92(17): p.1388-402.
[136] Brandes M. E., Wakefield L. M., Wahl S. M. Modulation of monocyte type I transforminggrowth factor-beta receptors by inflammatory stimuli. J Biol Chem.1991,266(29): p.19697-703.
[137] Tamura S., Morikawa Y., Iwanishi H., et al. Foxp1gene expression in projection neurons ofthe mouse striatum. Neuroscience.2004,124(2): p.261-7.
[138] Hu H., Wang B., Borde M., et al. Foxp1is an essential transcriptional regulator of B celldevelopment. Nat Immunol.2006,7(8): p.819-26.
[139] Spiteri E., Konopka G., Coppola G., et al. Identification of the transcriptional targets ofFOXP2, a gene linked to speech and language, in developing human brain. Am J HumGenet.2007,81(6): p.1144-57.
[140] Shu W., Lu M. M., Zhang Y., et al. Foxp2and Foxp1cooperatively regulate lung andesophagus development. Development.2007,134(10): p.1991-2000.
[141] Lu M. M., Li S., Yang H., et al. Foxp4: a novel member of the Foxp subfamily ofwinged-helix genes co-expressed with Foxp1and Foxp2in pulmonary and gut tissues.Mech Dev.2002,119Suppl1: p. S197-202.
[142] Burchill M. A., Yang J., Vogtenhuber C., et al. IL-2receptor beta-dependent STAT5activation is required for the development of Foxp3+regulatory T cells. J Immunol.2007,178(1): p.280-90.
[143] Kim H. P., Leonard W. J. CREB/ATF-dependent T cell receptor-induced FoxP3geneexpression: a role for DNA methylation. J Exp Med.2007,204(7): p.1543-51.
[144] Tone Y., Furuuchi K., Kojima Y., et al. Smad3and NFAT cooperate to induce Foxp3expression through its enhancer. Nat Immunol.2008,9(2): p.194-202.
[145] Chen Q., Kim Y. C., Laurence A., et al. IL-2controls the stability of Foxp3expression inTGF-beta-induced Foxp3+T cells in vivo. J Immunol.2011,186(11): p.6329-37.
[146] Rao S., Gerondakis S., Woltring D., et al. c-Rel is required for chromatin remodeling acrossthe IL-2gene promoter. J Immunol.2003,170(7): p.3724-31.
[147] Kitoh A., Ono M., Naoe Y., et al. Indispensable role of the Runx1-Cbfbeta transcriptioncomplex for in vivo-suppressive function of FoxP3+regulatory T cells. Immunity.2009,31(4): p.609-20.
[148] Yang X. O., Nurieva R., Martinez G. J., et al. Molecular antagonism and plasticity ofregulatory and inflammatory T cell programs. Immunity.2008,29(1): p.44-56.
[149] Zhou Z., Song X., Li B., et al. FOXP3and its partners: structural and biochemical insightsinto the regulation of FOXP3activity. Immunol Res.2008,42(1-3): p.19-28.
[150] Shah R., Medina-Martinez O., Chu L. F., et al. Expression of FoxP2during zebrafishdevelopment and in the adult brain. Int J Dev Biol.2006,50(4): p.435-8.
[151] Cheng L., Chong M., Fan W., et al. Molecular cloning, characterization, and developmentalexpression of foxp1in zebrafish. Dev Genes Evol.2007,217(10): p.699-707.
[152] Wen Y., Fang W., Xiang L. X., et al. Identification of Treg-like cells in Tetraodon: insightinto the origin of regulatory T subsets during early vertebrate evolution. Cell Mol Life Sci.68(15): p.2615-26.
[153] Goatly A., Bacon C. M., Nakamura S., et al. FOXP1abnormalities in lymphoma:translocation breakpoint mapping reveals insights into deregulated transcriptional control.Mod Pathol.2008,21(7): p.902-11.
[154] Lehmann O. J., Sowden J. C., Carlsson P., et al. Fox's in development and disease. TrendsGenet.2003,19(6): p.339-44.
[155] Bonkowsky J. L., Chien C. B. Molecular cloning and developmental expression of foxP2inzebrafish. Dev Dyn.2005,234(3): p.740-6.
[156] Vernes S. C., Nicod J., Elahi F. M., et al. Functional genetic analysis of mutationsimplicated in a human speech and language disorder. Hum Mol Genet.2006,15(21): p.3154-67.
[157] MacDermot K. D., Bonora E., Sykes N., et al. Identification of FOXP2truncation as a novelcause of developmental speech and language deficits. Am J Hum Genet.2005,76(6): p.1074-80.
[158] Lin G. L., Ellsaesser C. F., Clem L. W., et al. Phorbol ester/calcium ionophore activate fishleukocytes and induce long-term cultures. Dev Comp Immunol.1992,16(2-3): p.153-63.
[159] Edholm E. S., Stafford J. L., Quiniou S. M., et al. Channel catfish, Ictalurus punctatus,CD4-like molecules. Dev Comp Immunol.2007,31(2): p.172-87.
[160] Araki K., Akatsu K., Suetake H., et al. Characterization of CD8+leukocytes in fugu(Takifugu rubripes) with antiserum against fugu CD8alpha. Dev Comp Immunol.2008,32(7): p.850-8.
[161] Koumans-van Diepen J. C., Harmsen E. G., Rombout J. H. Immunocytochemical analysis ofmitogen responses of carp (Cyprinus carpio L.) peripheral blood leucocytes. Vet ImmunolImmunopathol.1994,42(2): p.209-19.
[162] Chen G., Gharib T. G., Huang C. C., et al. G. Discordant protein and mRNA expression inlung adenocarcinomas. Mol Cell Proteomics.2002,1(4): p.304-13.
[163] Tian Q., Stepaniants S. B., Mao M., et al. Integrated genomic and proteomic analyses ofgene expression in Mammalian cells. Mol Cell Proteomics.2004,3(10): p.960-9.
[164] Fontenot J. D., Rudensky A. Y. A well adapted regulatory contrivance: regulatory T celldevelopment and the forkhead family transcription factor Foxp3. Nat Immunol.2005,6(4):p.331-7.
[165] Zheng S. G., Wang J., Wang P., et al. A. IL-2is essential for TGF-beta to convert naiveCD4+CD25-cells to CD25+Foxp3+regulatory T cells and for expansion of these cells. JImmunol.2007,178(4): p.2018-27.
[166] Mantel P. Y., Ouaked N., Ruckert B., et al. Molecular mechanisms underlying FOXP3induction in human T cells. J Immunol.2006,176(6): p.3593-602.
[167] Tone M., Greene M. I. Cooperative regulatory events and Foxp3expression. Nat Immunol.12(1): p.14-6.
[168] Zheng Y., Josefowicz S., Chaudhry A., et al. Y. Role of conserved non-coding DNAelements in the Foxp3gene in regulatory T-cell fate. Nature.2010,463(7282): p.808-12.
[169] Baecher-Allan C., Brown J. A., Freeman G. J., et al. A. CD4+CD25high regulatory cells inhuman peripheral blood. J Immunol.2001,167(3): p.1245-53.
[170] Shevach E. M., Davidson T. S., Huter E. N., et al. Role of TGF-Beta in the induction ofFoxp3expression and T regulatory cell function. J Clin Immunol.2008,28(6): p.640-6.
[171] Nakamura K., Kitani A., Fuss I., et al. TGF-beta1plays an important role in the mechanismof CD4+CD25+regulatory T cell activity in both humans and mice. J Immunol.2004,172(2): p.834-42.
[172] Huber S., Stahl F. R., Schrader J., et al. Activin a promotes the TGF-beta-inducedconversion of CD4+CD25-T cells into Foxp3+induced regulatory T cells. J Immunol.2009,182(8): p.4633-40.
[173] Maganto-Garcia E., Bu D. X., Tarrio M. L., et al. Foxp3+-inducible regulatory T cellssuppress endothelial activation and leukocyte recruitment. J Immunol.2011,187(7): p.3521-9.
[174] Selvaraj R. K., Geiger T. L. A kinetic and dynamic analysis of Foxp3induced in T cells byTGF-beta. J Immunol.2007,178(12): p.7667-77.
[175] Watanabe M. A., Oda J. M., Amarante M. K., et al. Regulatory T cells and breast cancer:implications for immunopathogenesis. Cancer Metastasis Rev.2010,29(4): p.569-79.
[176] Ostroukhova M., Ray A. CD25+T cells and regulation of allergen-induced responses. CurrAllergy Asthma Rep.2005,5(1): p.35-41.
[177] Suri-Payer E., Fritzsching B. Regulatory T cells in experimental autoimmune disease.Springer Semin Immunopathol.2006,28(1): p.3-16.
[178] Ito T., Hanabuchi S., Wang Y. H., et al. Two functional subsets of FOXP3+regulatory Tcells in human thymus and periphery. Immunity.2008,28(6): p.870-80.
[179] Tuovinen H., Kekalainen E., Rossi L. H., et al. Cutting edge: human CD4-CD8-thymocytesexpress FOXP3in the absence of a TCR. J Immunol.2008,180(6): p.3651-4.
[180] Lim A., French M. A., Price P. CD4+and CD8+T cells expressing FoxP3in HIV-infectedpatients are phenotypically distinct and influenced by disease severity and antiretroviraltherapy. J Acquir Immune Defic Syndr.2009,51(3): p.248-57.
[181] Kiniwa Y., Miyahara Y., Wang H. Y., et al. CD8+Foxp3+regulatory T cells mediateimmunosuppression in prostate cancer. Clin Cancer Res.2007,13(23): p.6947-58.
[182] Chaput N., Louafi S., Bardier A., et al. Identification of CD8+CD25+Foxp3+suppressive Tcells in colorectal cancer tissue. Gut.2009,58(4): p.520-9.
[183] Engelmann P., Farkas K., Kis J., et al. Characterization of human invariant natural killer Tcells expressing FoxP3. Int Immunol.2011,23(8): p.473-84.
[184] Ouyang W., Rutz S., Crellin N. K., et al. Regulation and functions of the IL-10family ofcytokines in inflammation and disease. Annu Rev Immunol.2011,29: p.71-109.
[2] Govinden R., Bhoola K. D. Genealogy, expression, and cellular function of transforminggrowth factor-beta. Pharmacol Ther.2003,98(2): p.257-65.
[3] Gorelik L., Flavell R. A. Abrogation of TGFbeta signaling in T cells leads to spontaneous Tcell differentiation and autoimmune disease. Immunity.2000,12(2): p.171-81.
[4] Li M. O., Wan Y. Y., Sanjabi S., et al. Transforming growth factor-beta regulation ofimmune responses. Annu Rev Immunol.2006,24: p.99-146.
[5] Reiner S. L. Development in motion: helper T cells at work. Cell.2007,129(1): p.33-6.
[6] Gorelik L., Constant S., Flavell R. A. Mechanism of transforming growth factorbeta-induced inhibition of T helper type1differentiation. J Exp Med.2002,195(11): p.1499-505.
[7] Cerwenka A., Swain S. L. TGF-beta1: immunosuppressant and viability factor for Tlymphocytes. Microbes Infect.1999,1(15): p.1291-6.
[8] Kobayashi S., Yoshida K., Ward J. M., et al. Beta2-microglobulin-deficient backgroundameliorates lethal phenotype of the TGF-beta1null mouse. J Immunol.1999,163(7): p.4013-9.
[9] Horwitz D. A., Zheng S. G., Gray J. D. The role of the combination of IL-2and TGF-beta orIL-10in the generation and function of CD4+CD25+and CD8+regulatory T cell subsets. JLeukoc Biol.2003,74(4): p.471-8.
[10] Chen W., Jin W., Hardegen N., et al. Conversion of peripheral CD4+CD25-naive T cells toCD4+CD25+regulatory T cells by TGF-beta induction of transcription factor Foxp3. J ExpMed.2003,198(12): p.1875-86.
[11] Fantini M. C., Becker C., Monteleone G., et al. Cutting edge: TGF-beta induces a regulatoryphenotype in CD4+CD25-T cells through Foxp3induction and down-regulation of Smad7.J Immunol.2004,172(9): p.5149-53.
[12] Zheng S. G., Wang J. H., Gray J. D., et al. Natural and induced CD4+CD25+cells educateCD4+CD25-cells to develop suppressive activity: the role of IL-2, TGF-beta, and IL-10. JImmunol.2004,172(9): p.5213-21.
[13] Gershon R. K. A disquisition on suppressor T cells. Transplant Rev.1975,26: p.170-85.
[14] Cazac B. B., Roes J. TGF-beta receptor controls B cell responsiveness and induction of IgAin vivo. Immunity.2000,13(4): p.443-51.
[15] Stavnezer J. Regulation of antibody production and class switching by TGF-beta. JImmunol.1995,155(4): p.1647-51.
[16] Lebman D. A., Edmiston J. S. The role of TGF-beta in growth, differentiation, andmaturation of B lymphocytes. Microbes Infect.1999,1(15): p.1297-304.
[17] Rook A. H., Kehrl J. H., Wakefield L. M., et al. Effects of transforming growth factor betaon the functions of natural killer cells: depressed cytolytic activity and blunting of interferonresponsiveness. J Immunol.1986,136(10): p.3916-20.
[18] Bellone G., Aste-Amezaga M., Trinchieri G., et al. Regulation of NK cell functions byTGF-beta1. J Immunol.1995,155(3): p.1066-73.
[19] Hunter C. A., Bermudez L., Beernink H., et al. Transforming growth factor-beta inhibitsinterleukin-12-induced production of interferon-gamma by natural killer cells: a role fortransforming growth factor-beta in the regulation of T cell-independent resistance toToxoplasma gondii. Eur J Immunol.1995,25(4): p.994-1000.
[20] Steinman R. M., Hawiger D., Nussenzweig M. C. Tolerogenic dendritic cells. Annu RevImmunol.2003,21: p.685-711.
[21] Strobl H., Knapp W. TGF-beta1regulation of dendritic cells. Microbes Infect.1999,1(15):p.1283-90.
[22] Ashcroft G. S. Bidirectional regulation of macrophage function by TGF-beta. MicrobesInfect.1999,1(15): p.1275-82.
[23] Gruber B. L., Marchese M. J., Kew R. R. Transforming growth factor-beta1mediates mastcell chemotaxis. J Immunol.1994,152(12): p.5860-7.
[24] Olsson N., Piek E., ten Dijke P., et al. Human mast cell migration in response to members ofthe transforming growth factor-beta family. J Leukoc Biol.2000,67(3): p.350-6.
[25] Klion A. D., Nutman T. B. The role of eosinophils in host defense against helminth parasites.J Allergy Clin Immunol.2004,113(1): p.30-7.
[26] Munitz A., Levi-Schaffer F. Eosinophils:'new' roles for 'old' cells. Allergy.2004,59(3): p.268-75.
[27] Litman G. W., Cooper M. D. Why study the evolution of immunity? Nat Immunol.2007,8(6): p.547-8.
[28] Haddad G., Hanington P. C., Wilson E. C., et al. Molecular and functional characterizationof goldfish (Carassius auratus L.) transforming growth factor beta. Dev Comp Immunol.2008,32(6): p.654-63.
[29] Grayfer L., Belosevic M. Molecular characterization of tumor necrosis factor receptors1and2of the goldfish (Carassius aurutus L.). Mol Immunol.2009,46(11-12): p.2190-9.
[30] Cai Z., Gao C., Li L., et al. Bipolar properties of red seabream (Pagrus major) transforminggrowth factor-beta in induction of the leucocytes migration. Fish Shellfish Immunol.2010,28(4): p.695-700.
[31] Ohtsuka K., Gray J. D., Stimmler M. M., et al. Decreased production of TGF-beta bylymphocytes from patients with systemic lupus erythematosus. J Immunol.1998,160(5): p.2539-45.
[32] Dang H., Geiser A. G., Letterio J. J., et al. SLE-like autoantibodies and Sjogren'ssyndrome-like lymphoproliferation in TGF-beta knockout mice. J Immunol.1995,155(6): p.3205-12.
[33] Yaswen L., Kulkarni A. B., Fredrickson T., et al. Autoimmune manifestations in thetransforming growth factor-beta1knockout mouse. Blood.1996,87(4): p.1439-45.
[34] Holmdahl R., Bockermann R., Backlund J., et al. The molecular pathogenesis ofcollagen-induced arthritis in mice--a model for rheumatoid arthritis. Ageing Res Rev.2002,1(1): p.135-47.
[35] Thorbecke G. J., Shah R., Leu C. H., et al. Involvement of endogenous tumor necrosis factoralpha and transforming growth factor beta during induction of collagen type II arthritis inmice. Proc Natl Acad Sci U S A.1992,89(16): p.7375-9.
[36] Grewal I. S., Grewal K. D., Wong F. S., et al. Expression of transgene encoded TGF-beta inislets prevents autoimmune diabetes in NOD mice by a local mechanism. J Autoimmun.2002,19(1-2): p.9-22.
[37] Peng Y., Laouar Y., Li M. O., et al. TGF-beta regulates in vivo expansion ofFoxp3-expressing CD4+CD25+regulatory T cells responsible for protection againstdiabetes. Proc Natl Acad Sci U S A.2004,101(13): p.4572-7.
[38] Friese M. A., Wischhusen J., Wick W., et al. RNA interference targeting transforminggrowth factor-beta enhances NKG2D-mediated antiglioma immune response, inhibitsglioma cell migration and invasiveness, and abrogates tumorigenicity in vivo. Cancer Res.2004,64(20): p.7596-603.
[39] Stander M., Naumann U., Dumitrescu L., et al. Decorin gene transfer-mediated suppressionof TGF-beta synthesis abrogates experimental malignant glioma growth in vivo. Gene Ther.1998,5(9): p.1187-94.
[40] Chang H. L., Gillett N., Figari I., et al. Increased transforming growth factor beta expressioninhibits cell proliferation in vitro, yet increases tumorigenicity and tumor growth of Meth Asarcoma cells. Cancer Res.1993,53(18): p.4391-8.
[41] Fakhrai H., Dorigo O., Shawler D. L., et al. Eradication of established intracranial ratgliomas by transforming growth factor beta antisense gene therapy. Proc Natl Acad Sci U SA.1996,93(7): p.2909-14.
[42] Sutmuller R. P., van Duivenvoorde L. M., van Elsas A., et al. Synergism of cytotoxic Tlymphocyte-associated antigen4blockade and depletion of CD25(+) regulatory T cells inantitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic Tlymphocyte responses. J Exp Med.2001,194(6): p.823-32.
[43] Shimizu J., Yamazaki S., Sakaguchi S. Induction of tumor immunity by removingCD25+CD4+T cells: a common basis between tumor immunity and autoimmunity. JImmunol.1999,163(10): p.5211-8.
[44] Onizuka S., Tawara I., Shimizu J., et al. Tumor rejection by in vivo administration ofanti-CD25(interleukin-2receptor alpha) monoclonal antibody. Cancer Res.1999,59(13): p.3128-33.
[45] Scherf W., Burdach S., Hansen G. Reduced expression of transforming growth factor beta1exacerbates pathology in an experimental asthma model. Eur J Immunol.2005,35(1): p.198-206.
[46] Mallat Z., Gojova A., Marchiol-Fournigault C., et al. Inhibition of transforming growthfactor-beta signaling accelerates atherosclerosis and induces an unstable plaque phenotypein mice. Circ Res.2001,89(10): p.930-4.
[47] Lutgens E., Gijbels M., Smook M., et al. Transforming growth factor-beta mediates balancebetween inflammation and fibrosis during plaque progression. Arterioscler Thromb VascBiol.2002,22(6): p.975-82.
[48] Hansen G., McIntire J. J., Yeung V. P., et al. T. CD4(+) T helper cells engineered to producelatent TGF-beta1reverse allergen-induced airway hyperreactivity and inflammation. J ClinInvest.2000,105(1): p.61-70.
[49] Gorelik L., Fields P. E., Flavell R. A. Cutting edge: TGF-beta inhibits Th type2development through inhibition of GATA-3expression. J Immunol.2000,165(9): p.4773-7.
[50] Tafalla C., Coll J., Secombes C. J. Expression of genes related to the early immune responsein rainbow trout (Oncorhynchus mykiss) after viral haemorrhagic septicemia virus (VHSV)infection. Dev Comp Immunol.2005,29(7): p.615-26.
[51] Bridle A. R., Morrison R. N., Nowak B. F. The expression of immune-regulatory genes inrainbow trout, Oncorhynchus mykiss, during amoebic gill disease (AGD). Fish ShellfishImmunol.2006,20(3): p.346-64.
[52] Mulder I. E., Wadsworth S.,Secombes C. J. Cytokine expression in the intestine of rainbowtrout (Oncorhynchus mykiss) during infection with Aeromonas salmonicida. Fish ShellfishImmunol.2007,23(4): p.747-59.
[53] Scapigliati G., Buonocore F., Randelli E., et al. Cellular and molecular immune responses ofthe sea bass (Dicentrarchus labrax) experimentally infected with betanodavirus. FishShellfish Immunol.2010,28(2): p.303-11.
[54] Eder K. J., Clifford M. A., Hedrick R. P., et al. Expression of immune-regulatory genes injuvenile Chinook salmon following exposure to pesticides and infectious hematopoieticnecrosis virus (IHNV). Fish Shellfish Immunol.2008,25(5): p.508-16.
[55] Skugor S., Glover K. A., Nilsen F., et al. Local and systemic gene expression responses ofAtlantic salmon (Salmo salar L.) to infection with the salmon louse (Lepeophtheirussalmonis). BMC Genomics.2008,9: p.498.
[56] Robertson L. S., Ottinger C. A., Burdick S. M., et al. Development of a quantitative assay tomeasure expression of transforming growth factor beta (TGF-beta) in Lost River sucker(Deltistes luxatus) and shortnose sucker (Chasmistes brevirostris) and evaluation ofpotential pitfalls in use with field-collected samples. Fish Shellfish Immunol.2012,32(5): p.890-8
[57] Huminiecki L., Goldovsky L., Freilich S., et al. Emergence, development and diversificationof the TGF-beta signalling pathway within the animal kingdom. BMC Evol Biol.2009,9: p.28.
[58] Annes J. P., Munger J. S.,Rifkin D. B. Making sense of latent TGFbeta activation. J Cell Sci.2003,116(Pt2): p.217-24.
[59] Crawford S. E., Stellmach V., Murphy-Ullrich J. E., et al. Thrombospondin-1is a majoractivator of TGF-beta1in vivo. Cell.1998,93(7): p.1159-70.
[60] Yehualaeshet T., O'Connor R., Green-Johnson J., et al. Activation of rat alveolarmacrophage-derived latent transforming growth factor beta-1by plasmin requiresinteraction with thrombospondin-1and its cell surface receptor, CD36. Am J Pathol.1999,155(3): p.841-51.
[61] Annes J. P., Chen Y., Munger J. S., et al. Integrin alphaVbeta6-mediated activation of latentTGF-beta requires the latent TGF-beta binding protein-1. J Cell Biol.2004,165(5): p.723-34.
[62] Munger J. S., Harpel J. G., Giancotti F. G., et al. Interactions between growth factors andintegrins: latent forms of transforming growth factor-beta are ligands for the integrinalphavbeta1. Mol Biol Cell.1998,9(9): p.2627-38.
[63] Munger J. S., Harpel J. G., Gleizes P. E., et al. Latent transforming growth factor-beta:structural features and mechanisms of activation. Kidney Int.1997,51(5): p.1376-82.
[64] Massague J. TGF-beta signal transduction. Annu Rev Biochem.1998,67: p.753-91.
[65] ten Dijke P., Hill C. S. New insights into TGF-beta-Smad signalling. Trends Biochem Sci.2004,29(5): p.265-73.
[66] Huse M., Muir T. W., Xu L., et al. The TGF beta receptor activation process: an inhibitor-tosubstrate-binding switch. Mol Cell.2001,8(3): p.671-82.
[67] Shi Y., Massague J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus.Cell.2003,113(6): p.685-700.
[68] Engel M. E., McDonnell M. A., Law B. K., et al. Interdependent SMAD and JNK signalingin transforming growth factor-beta-mediated transcription. J Biol Chem.1999,274(52): p.37413-20.
[69] Yu L., Hebert M. C., Zhang Y. E. TGF-beta receptor-activated p38MAP kinase mediatesSmad-independent TGF-beta responses. Embo J.2002,21(14): p.3749-59.
[70] Kohli G., Hu S., Clelland E., et al. Cloning of transforming growth factor-beta1(TGF-beta1) and its type II receptor from zebrafish ovary and role of TGF-beta1in oocyte maturation.Endocrinology.2003,144(5): p.1931-41.
[71] Wan Y. Y., Flavell R. A. TGF-beta and regulatory T cell in immunity and autoimmunity. JClin Immunol.2008,28(6): p.647-59.
[72] Wan Y. Y., Flavell R. A. Identifying Foxp3-expressing suppressor T cells with a bicistronicreporter. Proc Natl Acad Sci U S A.2005,102(14): p.5126-31.
[73] Marie J. C., Letterio J. J., Gavin M., et al. TGF-beta1maintains suppressor function andFoxp3expression in CD4+CD25+regulatory T cells. J Exp Med.2005,201(7): p.1061-7.
[74] Mamura M., Lee W., Sullivan T. J., et al. CD28disruption exacerbates inflammation inTgf-beta1-/-mice: in vivo suppression by CD4+CD25+regulatory T cells independent ofautocrine TGF-beta1. Blood.2004,103(12): p.4594-601.
[75] Fontenot J. D., Gavin M. A., Rudensky A. Y. Foxp3programs the development and functionof CD4+CD25+regulatory T cells. Nat Immunol.2003,4(4): p.330-6.
[76] Hori S., Nomura T., Sakaguchi S. Control of regulatory T cell development by thetranscription factor Foxp3. Science.2003,299(5609): p.1057-61.
[77] Sakaguchi S., Sakaguchi N., Asano M., et al. Immunologic self-tolerance maintained byactivated T cells expressing IL-2receptor alpha-chains (CD25). Breakdown of a singlemechanism of self-tolerance causes various autoimmune diseases. J Immunol.1995,155(3):p.1151-64.
[78] Khattri R., Cox T., Yasayko S. A.,Ramsdell F. An essential role for Scurfin in CD4+CD25+T regulatory cells. Nat Immunol.2003,4(4): p.337-42.
[79] Ochs H. D., Ziegler S. F., Torgerson T. R. FOXP3acts as a rheostat of the immune response.Immunol Rev.2005,203: p.156-64.
[80] Ziegler S. F. FOXP3: of mice and men. Annu Rev Immunol.2006,24: p.209-26.
[81] Bennett C. L., Christie J., Ramsdell F., et al. The immune dysregulation,polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations ofFOXP3. Nat Genet.2001,27(1): p.20-1.
[82] Chatila T. A., Blaeser F., Ho N., et al. M. JM2, encoding a fork head-related protein, ismutated in X-linked autoimmunity-allergic disregulation syndrome. J Clin Invest.2000,106(12): p. R75-81.
[83] Sakaguchi S., Miyara M., Costantino C. M., et al. FOXP3+regulatory T cells in the humanimmune system. Nat Rev Immunol.10(7): p.490-500.
[84] Yagi H., Nomura T., Nakamura K., et al. Crucial role of FOXP3in the development andfunction of human CD25+CD4+regulatory T cells. Int Immunol.2004,16(11): p.1643-56.
[85] Wan Y. Y., Flavell R. A. Regulatory T-cell functions are subverted and converted owing toattenuated Foxp3expression. Nature.2007,445(7129): p.766-70.
[86] Mitra S., Alnabulsi A., Secombes C. J., et al. Identification and characterization of thetranscription factors involved in T-cell development, t-bet, stat6and foxp3, within thezebrafish, Danio rerio. Febs J.2010,277(1): p.128-47.
[87] Quintana F. J., Iglesias A. H., Farez M. F., et al. Adaptive autoimmunity and Foxp3-basedimmunoregulation in zebrafish. PLoS One.2010,5(3): p. e9478.
[88] Wang T., Monte M. M., Huang W., et al. Identification of two FoxP3genes in rainbow trout(Oncorhynchus mykiss) with differential induction patterns. Mol Immunol.2010,47(16): p.2563-74.
[89] Zhang Z., Chi H., Niu C., et al. Molecular cloning and characterization of Foxp3in Atlanticsalmon (Salmo salar). Fish Shellfish Immunol.201130(3): p.902-9.
[90] Kaestner K. H., Knochel W., Martinez D. E. Unified nomenclature for the wingedhelix/forkhead transcription factors. Genes Dev.2000,14(2): p.142-6.
[91] Kaufmann E., Knochel W. Five years on the wings of fork head. Mech Dev.1996,57(1): p.3-20.
[92] Schubert L. A., Jeffery E., Zhang Y., et al. Scurfin (FOXP3) acts as a repressor oftranscription and regulates T cell activation. J Biol Chem.2001,276(40): p.37672-9.
[93] Kasprowicz D. J., Smallwood P. S., Tyznik A. J., et al. Scurfin (FoxP3) controlsT-dependent immune responses in vivo through regulation of CD4+T cell effector function.J Immunol.2003,171(3): p.1216-23.
[94] Bettelli E., Dastrange M., Oukka M. Foxp3interacts with nuclear factor of activated T cellsand NF-kappa B to repress cytokine gene expression and effector functions of T helper cells.Proc Natl Acad Sci U S A.2005,102(14): p.5138-43.
[95] Blobe G. C., Schiemann W. P., Lodish H. F. Role of transforming growth factor beta inhuman disease. N Engl J Med.2000,342(18): p.1350-8.
[96] Li M. O., Flavell R. A. TGF-beta: a master of all T cell trades. Cell.2008,134(3): p.392-404.
[97] Saxena V., Lienesch D. W., Zhou M., et al. Dual roles of immunoregulatory cytokineTGF-beta in the pathogenesis of autoimmunity-mediated organ damage. J Immunol.2008,180(3): p.1903-12.
[98] Zhang L., Yi H., Xia X. P., et al. Transforming growth factor-beta: an important role inCD4+CD25+regulatory T cells and immune tolerance. Autoimmunity.2006,39(4): p.269-76.
[99] Letterio J. J., Roberts A. B. Regulation of immune responses by TGF-beta. Annu RevImmunol.1998,16: p.137-61.
[100] Wahl S. M. Transforming growth factor beta: the good, the bad, and the ugly. J Exp Med.1994,180(5): p.1587-90.
[101] Li B., Samanta A., Song X., et al. FOXP3ensembles in T-cell regulation. Immunol Rev.2006,212: p.99-113.
[102] Wan Y. Y., Flavell R. A.'Yin-Yang' functions of transforming growth factor-beta and Tregulatory cells in immune regulation. Immunol Rev.2007,220: p.199-213.
[103] Laouar Y., Sutterwala F. S., Gorelik L., et al. Transforming growth factor-beta controls Thelper type1cell development through regulation of natural killer cell interferon-gamma.Nat Immunol.2005,6(6): p.600-7.
[104] Kadowaki T., Yasui Y., Takahashi Y., et al. Comparative immunological analysis of innateimmunity activation after oral administration of wheat fermented extract to teleost fish.Anticancer Res.2009,29(11): p.4871-7.
[105] Sepulcre M. P., Pelegrin P., Mulero V., et al. Characterisation of gilthead seabreamacidophilic granulocytes by a monoclonal antibody unequivocally points to theirinvolvement in fish phagocytic response. Cell Tissue Res.2002,308(1): p.97-102.
[106] Pettersen E. F., Bjerknes R.,Wergeland H. I. Studies of Atlantic salmon (Salmo salar L.)blood, spleen and head kidney leucocytes using specific monoclonal antibodies,immunohistochemistry and flow cytometry. Fish Shellfish Immunol.2000,10(8): p.695-710.
[107] Boschi I., Randelli E., Buonocore F., et al. Transcription of T cell-related genes in teleostfish, and the European sea bass (Dicentrarchus labrax) as a model. Fish Shellfish Immunol.2011,31(5): p.655-62.
[108] Zwollo P., Cole S., Bromage E., et al. B cell heterogeneity in the teleost kidney: evidencefor a maturation gradient from anterior to posterior kidney. J Immunol.2005,174(11): p.6608-16.
[109] Rodrigues P. N., Hermsen T. T., Rombout J. H., et al. Detection of MHC class II transcriptsin lymphoid tissues of the common carp (Cyprinus carpio L.). Dev Comp Immunol.1995,19(6): p.483-96.
[110] Kemenade B., Groeneveld A., Rens B., et al. Characterization of Macrophages andNeutrophilic Granulocytes from the Pronephros of Carp (Cyprinus Carpio). J Exp Biol.1994,187(1): p.143-58.
[111] Tafalla C., Aranguren R., Secombes C. J., et al. Molecular characterisation of sea bream(Sparus aurata) transforming growth factor beta1. Fish Shellfish Immunol.2003,14(5): p.405-21.
[112] Grayfer L., Hodgkinson J. W., Hitchen S. J., et al. Characterization and functional analysisof goldfish (Carassius auratus L.) interleukin-10. Mol Immunol.2011,48(4): p.563-71.
[113] Grayfer L., Walsh J. G., Belosevic M. Characterization and functional analysis of goldfish(Carassius auratus L.) tumor necrosis factor-alpha. Dev Comp Immunol.2008,32(5): p.532-43.
[114] Grayfer L., Belosevic M. Molecular characterization, expression and functional analysis ofgoldfish (Carassius aurutus L.) interferon gamma. Dev Comp Immunol.2009,33(2): p.235-46.
[115] Zou J., Peddie S., Scapigliati G., et al. Functional characterisation of the recombinant tumornecrosis factors in rainbow trout, Oncorhynchus mykiss. Dev Comp Immunol.2003,27(9):p.813-22.
[116] Saeij J. P., Stet R. J., de Vries B. J., et al. Molecular and functional characterization of carpTNF: a link between TNF polymorphism and trypanotolerance? Dev Comp Immunol.2003,27(1): p.29-41.
[117] Lopez-Munoz A., Roca F. J., Meseguer J., et al. New insights into the evolution of IFNs:zebrafish group II IFNs induce a rapid and transient expression of IFN-dependent genes anddisplay powerful antiviral activities. J Immunol.2009,182(6): p.3440-9.
[118] Arts J. A., Tijhaar E. J., Chadzinska M., et al. Functional analysis of carp interferon-gamma:evolutionary conservation of classical phagocyte activation. Fish Shellfish Immunol.2010,29(5): p.793-802.
[119] Stolte E. H., Savelkoul H. F., Wiegertjes G., et al. Differential expression of twointerferon-gamma genes in common carp (Cyprinus carpio L.). Dev Comp Immunol.2008,32(12): p.1467-81.
[120] Dijkstra J. M., Somamoto T., Moore L., et al. Identification and characterization of a secondCD4-like gene in teleost fish. Mol Immunol.2006,43(5): p.410-9.
[121] Sun X. F., Shang N., Hu W., et al. Molecular cloning and characterization of carp (Cyprinuscarpio L.) CD8beta and CD4-like genes. Fish Shellfish Immunol.2007,23(6): p.1242-55.
[122] Fischer U., Utke K., Ototake M., et al. Adaptive cell-mediated cytotoxicity againstallogeneic targets by CD8-positive lymphocytes of rainbow trout (Oncorhynchus mykiss).Dev Comp Immunol.2003,27(4): p.323-37.
[123] Hetland D. L., Jorgensen S. M., Skjodt K., et al. In situ localisation of majorhistocompatibility complex class I and class II and CD8positive cells in infectious salmonanaemia virus (ISAV)-infected Atlantic salmon. Fish Shellfish Immunol.2010,28(1): p.30-9.
[124] Picchietti S., Guerra L., Buonocore F., et al. Lymphocyte differentiation in sea bass thymus:CD4and CD8-alpha gene expression studies. Fish Shellfish Immunol.2009,27(1): p.50-6.
[125] Xiao F. S., Wang Y. P., Yan W., et al. Ig heavy chain genes and their locus in grass carpCtenopharyngodon idella. Fish Shellfish Immunol.2010,29(4): p.594-9.
[126] Ronneseth A., Wergeland H. I., Pettersen E. F. Neutrophils and B-cells in Atlantic cod(Gadus morhua L.). Fish Shellfish Immunol.2007,23(3): p.493-503.
[127] Inman G. J., Nicolas F. J., Hill C. S. Nucleocytoplasmic shuttling of Smads2,3, and4permits sensing of TGF-beta receptor activity. Mol Cell.2002,10(2): p.283-94.
[128] Liu Y., Zhang P., Li J., et al. A critical function for TGF-beta signaling in the developmentof natural CD4+CD25+Foxp3+regulatory T cells. Nat Immunol.2008,9(6): p.632-40.
[129] Markell L. M., Masiuk K. E., Blazanin N., et al. Pharmacologic inhibition of ALK5causesselective induction of terminal differentiation in mouse keratinocytes expressing oncogenicHRAS. Mol Cancer Res.2011,9(6): p.746-56.
[130] Mallet C., Vittet D., Feige J. J., et al. TGFbeta1induces vasculogenesis and inhibitsangiogenic sprouting in an embryonic stem cell differentiation model: respectivecontribution of ALK1and ALK5. Stem Cells.2006,24(11): p.2420-7.
[131] Miyazono K. TGF-beta/SMAD signaling and its involvement in tumor progression. BiolPharm Bull.2000,23(10): p.1125-30.
[132] Miyazono K., ten Dijke P., Heldin C. H. TGF-beta signaling by Smad proteins. AdvImmunol.2000,75: p.115-57.
[133] Ebisawa T., Fukuchi M., Murakami G., et al. Smurf1interacts with transforming growthfactor-beta type I receptor through Smad7and induces receptor degradation. J Biol Chem.2001,276(16): p.12477-80.
[134] Mitchell H., Choudhury A., Pagano R. E., et al. Ligand-dependent and-independenttransforming growth factor-beta receptor recycling regulated by clathrin-mediatedendocytosis and Rab11. Mol Biol Cell.2004,15(9): p.4166-78.
[135] de Caestecker M. P., Piek E., Roberts A. B. Role of transforming growth factor-betasignaling in cancer. J Natl Cancer Inst.2000,92(17): p.1388-402.
[136] Brandes M. E., Wakefield L. M., Wahl S. M. Modulation of monocyte type I transforminggrowth factor-beta receptors by inflammatory stimuli. J Biol Chem.1991,266(29): p.19697-703.
[137] Tamura S., Morikawa Y., Iwanishi H., et al. Foxp1gene expression in projection neurons ofthe mouse striatum. Neuroscience.2004,124(2): p.261-7.
[138] Hu H., Wang B., Borde M., et al. Foxp1is an essential transcriptional regulator of B celldevelopment. Nat Immunol.2006,7(8): p.819-26.
[139] Spiteri E., Konopka G., Coppola G., et al. Identification of the transcriptional targets ofFOXP2, a gene linked to speech and language, in developing human brain. Am J HumGenet.2007,81(6): p.1144-57.
[140] Shu W., Lu M. M., Zhang Y., et al. Foxp2and Foxp1cooperatively regulate lung andesophagus development. Development.2007,134(10): p.1991-2000.
[141] Lu M. M., Li S., Yang H., et al. Foxp4: a novel member of the Foxp subfamily ofwinged-helix genes co-expressed with Foxp1and Foxp2in pulmonary and gut tissues.Mech Dev.2002,119Suppl1: p. S197-202.
[142] Burchill M. A., Yang J., Vogtenhuber C., et al. IL-2receptor beta-dependent STAT5activation is required for the development of Foxp3+regulatory T cells. J Immunol.2007,178(1): p.280-90.
[143] Kim H. P., Leonard W. J. CREB/ATF-dependent T cell receptor-induced FoxP3geneexpression: a role for DNA methylation. J Exp Med.2007,204(7): p.1543-51.
[144] Tone Y., Furuuchi K., Kojima Y., et al. Smad3and NFAT cooperate to induce Foxp3expression through its enhancer. Nat Immunol.2008,9(2): p.194-202.
[145] Chen Q., Kim Y. C., Laurence A., et al. IL-2controls the stability of Foxp3expression inTGF-beta-induced Foxp3+T cells in vivo. J Immunol.2011,186(11): p.6329-37.
[146] Rao S., Gerondakis S., Woltring D., et al. c-Rel is required for chromatin remodeling acrossthe IL-2gene promoter. J Immunol.2003,170(7): p.3724-31.
[147] Kitoh A., Ono M., Naoe Y., et al. Indispensable role of the Runx1-Cbfbeta transcriptioncomplex for in vivo-suppressive function of FoxP3+regulatory T cells. Immunity.2009,31(4): p.609-20.
[148] Yang X. O., Nurieva R., Martinez G. J., et al. Molecular antagonism and plasticity ofregulatory and inflammatory T cell programs. Immunity.2008,29(1): p.44-56.
[149] Zhou Z., Song X., Li B., et al. FOXP3and its partners: structural and biochemical insightsinto the regulation of FOXP3activity. Immunol Res.2008,42(1-3): p.19-28.
[150] Shah R., Medina-Martinez O., Chu L. F., et al. Expression of FoxP2during zebrafishdevelopment and in the adult brain. Int J Dev Biol.2006,50(4): p.435-8.
[151] Cheng L., Chong M., Fan W., et al. Molecular cloning, characterization, and developmentalexpression of foxp1in zebrafish. Dev Genes Evol.2007,217(10): p.699-707.
[152] Wen Y., Fang W., Xiang L. X., et al. Identification of Treg-like cells in Tetraodon: insightinto the origin of regulatory T subsets during early vertebrate evolution. Cell Mol Life Sci.68(15): p.2615-26.
[153] Goatly A., Bacon C. M., Nakamura S., et al. FOXP1abnormalities in lymphoma:translocation breakpoint mapping reveals insights into deregulated transcriptional control.Mod Pathol.2008,21(7): p.902-11.
[154] Lehmann O. J., Sowden J. C., Carlsson P., et al. Fox's in development and disease. TrendsGenet.2003,19(6): p.339-44.
[155] Bonkowsky J. L., Chien C. B. Molecular cloning and developmental expression of foxP2inzebrafish. Dev Dyn.2005,234(3): p.740-6.
[156] Vernes S. C., Nicod J., Elahi F. M., et al. Functional genetic analysis of mutationsimplicated in a human speech and language disorder. Hum Mol Genet.2006,15(21): p.3154-67.
[157] MacDermot K. D., Bonora E., Sykes N., et al. Identification of FOXP2truncation as a novelcause of developmental speech and language deficits. Am J Hum Genet.2005,76(6): p.1074-80.
[158] Lin G. L., Ellsaesser C. F., Clem L. W., et al. Phorbol ester/calcium ionophore activate fishleukocytes and induce long-term cultures. Dev Comp Immunol.1992,16(2-3): p.153-63.
[159] Edholm E. S., Stafford J. L., Quiniou S. M., et al. Channel catfish, Ictalurus punctatus,CD4-like molecules. Dev Comp Immunol.2007,31(2): p.172-87.
[160] Araki K., Akatsu K., Suetake H., et al. Characterization of CD8+leukocytes in fugu(Takifugu rubripes) with antiserum against fugu CD8alpha. Dev Comp Immunol.2008,32(7): p.850-8.
[161] Koumans-van Diepen J. C., Harmsen E. G., Rombout J. H. Immunocytochemical analysis ofmitogen responses of carp (Cyprinus carpio L.) peripheral blood leucocytes. Vet ImmunolImmunopathol.1994,42(2): p.209-19.
[162] Chen G., Gharib T. G., Huang C. C., et al. G. Discordant protein and mRNA expression inlung adenocarcinomas. Mol Cell Proteomics.2002,1(4): p.304-13.
[163] Tian Q., Stepaniants S. B., Mao M., et al. Integrated genomic and proteomic analyses ofgene expression in Mammalian cells. Mol Cell Proteomics.2004,3(10): p.960-9.
[164] Fontenot J. D., Rudensky A. Y. A well adapted regulatory contrivance: regulatory T celldevelopment and the forkhead family transcription factor Foxp3. Nat Immunol.2005,6(4):p.331-7.
[165] Zheng S. G., Wang J., Wang P., et al. A. IL-2is essential for TGF-beta to convert naiveCD4+CD25-cells to CD25+Foxp3+regulatory T cells and for expansion of these cells. JImmunol.2007,178(4): p.2018-27.
[166] Mantel P. Y., Ouaked N., Ruckert B., et al. Molecular mechanisms underlying FOXP3induction in human T cells. J Immunol.2006,176(6): p.3593-602.
[167] Tone M., Greene M. I. Cooperative regulatory events and Foxp3expression. Nat Immunol.12(1): p.14-6.
[168] Zheng Y., Josefowicz S., Chaudhry A., et al. Y. Role of conserved non-coding DNAelements in the Foxp3gene in regulatory T-cell fate. Nature.2010,463(7282): p.808-12.
[169] Baecher-Allan C., Brown J. A., Freeman G. J., et al. A. CD4+CD25high regulatory cells inhuman peripheral blood. J Immunol.2001,167(3): p.1245-53.
[170] Shevach E. M., Davidson T. S., Huter E. N., et al. Role of TGF-Beta in the induction ofFoxp3expression and T regulatory cell function. J Clin Immunol.2008,28(6): p.640-6.
[171] Nakamura K., Kitani A., Fuss I., et al. TGF-beta1plays an important role in the mechanismof CD4+CD25+regulatory T cell activity in both humans and mice. J Immunol.2004,172(2): p.834-42.
[172] Huber S., Stahl F. R., Schrader J., et al. Activin a promotes the TGF-beta-inducedconversion of CD4+CD25-T cells into Foxp3+induced regulatory T cells. J Immunol.2009,182(8): p.4633-40.
[173] Maganto-Garcia E., Bu D. X., Tarrio M. L., et al. Foxp3+-inducible regulatory T cellssuppress endothelial activation and leukocyte recruitment. J Immunol.2011,187(7): p.3521-9.
[174] Selvaraj R. K., Geiger T. L. A kinetic and dynamic analysis of Foxp3induced in T cells byTGF-beta. J Immunol.2007,178(12): p.7667-77.
[175] Watanabe M. A., Oda J. M., Amarante M. K., et al. Regulatory T cells and breast cancer:implications for immunopathogenesis. Cancer Metastasis Rev.2010,29(4): p.569-79.
[176] Ostroukhova M., Ray A. CD25+T cells and regulation of allergen-induced responses. CurrAllergy Asthma Rep.2005,5(1): p.35-41.
[177] Suri-Payer E., Fritzsching B. Regulatory T cells in experimental autoimmune disease.Springer Semin Immunopathol.2006,28(1): p.3-16.
[178] Ito T., Hanabuchi S., Wang Y. H., et al. Two functional subsets of FOXP3+regulatory Tcells in human thymus and periphery. Immunity.2008,28(6): p.870-80.
[179] Tuovinen H., Kekalainen E., Rossi L. H., et al. Cutting edge: human CD4-CD8-thymocytesexpress FOXP3in the absence of a TCR. J Immunol.2008,180(6): p.3651-4.
[180] Lim A., French M. A., Price P. CD4+and CD8+T cells expressing FoxP3in HIV-infectedpatients are phenotypically distinct and influenced by disease severity and antiretroviraltherapy. J Acquir Immune Defic Syndr.2009,51(3): p.248-57.
[181] Kiniwa Y., Miyahara Y., Wang H. Y., et al. CD8+Foxp3+regulatory T cells mediateimmunosuppression in prostate cancer. Clin Cancer Res.2007,13(23): p.6947-58.
[182] Chaput N., Louafi S., Bardier A., et al. Identification of CD8+CD25+Foxp3+suppressive Tcells in colorectal cancer tissue. Gut.2009,58(4): p.520-9.
[183] Engelmann P., Farkas K., Kis J., et al. Characterization of human invariant natural killer Tcells expressing FoxP3. Int Immunol.2011,23(8): p.473-84.
[184] Ouyang W., Rutz S., Crellin N. K., et al. Regulation and functions of the IL-10family ofcytokines in inflammation and disease. Annu Rev Immunol.2011,29: p.71-109.