Increased Th17 and Regulatory T Cell Responses in EBV-Induced Gene 3-Deficient Mice Lead to Marginally Enhanced Development of Autoimmune Encephalomyelitis
Increased Th17 and Regulatory T Cell Responses in EBV-Induced Gene 3-Deficient Mice Lead to Marginally Enhanced Development of Autoimmune Encephalomyelitis
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DOI：
10.4049/jimmunol.1100106
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发表时间：
2012-04-01
影响因子：
4.4
通讯作者：
Bai, Xue-Feng
中科院分区：
文献类型：
--
作者：
Liu, Jin-Qing;Liu, Zhenzhen;Bai, Xue-Feng
EB病毒诱导基因3（EBI 3）编码的蛋白质可以与IL-27 P28和IL-12 P35形成异二聚体，从而形成IL-27和IL-35。IL-27和IL-35可能分别通过抑制Th 17分化和促进Foxp 3（+）调节性T（Treg）细胞的抑制作用来影响自身免疫。在这项研究中，我们评估了EBI 3缺陷小鼠缺乏IL-27和IL-35的实验性自身免疫性脑脊髓炎（EAE）的发展。我们发现，髓鞘少突胶质细胞糖蛋白肽免疫导致EBI 3缺陷型C57 BL 6和2D 2 TCR转基因小鼠中EAE的发展略有增强。EBI 3缺乏导致CNS中Th 17和Th 1应答显著增加，外周淋巴器官中IL-2和IL-17的T细胞产生增加。EBI 3缺陷型和EBI 3充足型2D 2 T细胞在Rag 1（-/-）小鼠中诱导EAE的能力相同;然而，2D 2 T细胞在EBI 3（-/-）Rag 1（-/-）小鼠中诱导的疾病比在Rag 1（-/-）小鼠中更严重。EBI 3缺陷小鼠外周淋巴器官中CD 4（+）Foxp 3（+）Treg细胞数量增加。更引人注目的是，EBI 3缺陷型Treg细胞在体外和体内具有更强的抑制功能。因此，我们的数据支持EBI 3在Th 17、Th 1、IL-2和Treg应答中的抑制作用。尽管这些观察结果与IL-27的已知功能一致，但IL-35对Treg细胞的抑制功能的贡献在该模型中并不明显。EBI 3（-/-）小鼠中Treg反应的增加可以解释为什么与野生型小鼠相比，EAE的发展仅适度增强。免疫学杂志，2012，188：3099-3106。
EBV-induced gene 3 (EBI3)-encoded protein can form heterodimers with IL-27P28 and IL-12P35 to form IL-27 and IL-35. IL-27 and IL-35 may influence autoimmunity by inhibiting Th17 differentiation and facilitating the inhibitory roles of Foxp3(+) regulatory T (Treg) cells, respectively. In this study, we have evaluated the development of experimental autoimmune encephalomyelitis (EAE) in EBI3-deficient mice that lack both IL-27 and IL-35. We found that myelin oligodendrocyte glycoprotein peptide immunization resulted in marginally enhanced EAE development in EBI3-deficient C57BL6 and 2D2 TCR-transgenic mice. EBI3 deficiency resulted in significantly increased Th17 and Th1 responses in the CNS and increased T cell production of IL-2 and IL-17 in the peripheral lymphoid organs. EBI3-deficient and -sufficient 2D2 T cells had equal ability in inducing EAE in Rag1(-/-) mice; however, more severe disease was induced in EBI3(-/-) Rag1(-/-) mice than in Rag1(-/-) mice by 2D2 T cells. EBI3-deficient mice had increased numbers of CD4(+)Foxp3(+) Treg cells in peripheral lymphoid organs. More strikingly, EBI3-deficient Treg cells had more potent suppressive functions in vitro and in vivo. Thus, our data support an inhibitory role for EBI3 in Th17, Th1, IL-2, and Treg responses. Although these observations are consistent with the known functions of IL-27, the IL-35 contribution to the suppressive functions of Treg cells is not evident in this model. Increased Treg responses in EBI3(-/-) mice may explain why the EAE development is only modestly enhanced compared with wild-type mice. The Journal of Immunology, 2012, 188: 3099-3106.