Korn Thomas, Mitsdoerffer Meike, Croxford Andrew L, Awasthi Amit, Dardalhon Valérie A, Galileos George, Vollmar Patrick, Stritesky Gretta L, Kaplan Mark H, Waisman Ari, Kuchroo Vijay K, Oukka Mohamed
Technische Universität München, Department of Neurology, Ismaninger Strasse 22, 81675 München, Germany.
Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18460-5. doi: 10.1073/pnas.0809850105. Epub 2008 Nov 17.
The conditions leading to the induction of adaptive Foxp3(+) regulatory T cells (T-regs) from peripheral T cells in vivo are incompletely understood. Here, we show that unresponsiveness of T cells to IL-6 by T cell-selective deletion of gp130 or immunization of wild-type mice with antigen in incomplete Freund's adjuvant (IFA), which fails to induce IL-6, promotes the conversion of peripheral CD4(+) T cells into adaptive Foxp3(+) T-regs. Thus, both T cell-conditional gp130 knockout (KO) mice immunized with MOG35-55 in complete Freund's adjuvant (CFA) and wild-type mice immunized with MOG35-55 in IFA develop overwhelming antigen-specific T-reg responses and are protected from experimental autoimmune encephalomyelitis (EAE). Depletion of T-regs restores T helper (Th)17 responses and clinical EAE in MOG/CFA-immunized T cell-conditional gp130 KO mice, but not in MOG/IFA-immunized wild-type mice. We conclude that in the absence of T-regs, IL-6 signaling is dispensable for the induction of Th17 cells, and alternative pathways exist to induce Th17 cells and EAE in the absence of IL-6 signaling. However, IL-6 signaling is dominant in inhibiting the conversion of conventional T cells into Foxp3(+) T-regs in vivo, and in the absence of IL-6 signaling, no other cytokine can substitute in inhibiting T-reg conversion. These data identify IL-6 as an important target to modulate autoimmune responses and chronic inflammation.
体内外周T细胞诱导适应性Foxp3(+)调节性T细胞（Tregs）的条件尚未完全明确。在此，我们发现通过T细胞选择性缺失gp130或用不完全弗氏佐剂（IFA）免疫野生型小鼠（IFA不能诱导IL-6）使T细胞对IL-6无反应，可促进外周CD4(+) T细胞转化为适应性Foxp3(+) Tregs。因此，用完全弗氏佐剂（CFA）免疫MOG35-55的T细胞条件性gp130基因敲除（KO）小鼠以及用IFA免疫MOG35-55的野生型小鼠，均会产生强烈的抗原特异性Treg反应，并对实验性自身免疫性脑脊髓炎（EAE）具有保护作用。在MOG/CFA免疫的T细胞条件性gp130 KO小鼠中，去除Tregs可恢复辅助性T细胞（Th）17反应和临床EAE，但在MOG/IFA免疫的野生型小鼠中则不然。我们得出结论，在没有Tregs的情况下，IL-6信号对于Th17细胞的诱导是可有可无的，并且在没有IL-6信号的情况下存在诱导Th17细胞和EAE的替代途径。然而，IL-6信号在体内抑制常规T细胞转化为Foxp3(+) Tregs方面占主导地位，并且在没有IL-6信号的情况下，没有其他细胞因子可以替代其抑制Treg转化作用。这些数据表明IL-6是调节自身免疫反应和慢性炎症的重要靶点。
