4-1BB Triggering Ameliorates Experimental Autoimmune Encephalomyelitis by Modulating the Balance between Th17 and Regulatory T Cells
4-1BB Triggering Ameliorates Experimental Autoimmune Encephalomyelitis by Modulating the Balance between Th17 and Regulatory T Cells
复制标题
DOI：
10.4049/jimmunol.1002681
复制
发表时间：
2011-08-01
影响因子：
4.4
通讯作者：
Kwon, Byoung S.
中科院分区：
文献类型：
--
作者：
Kim, Young H.;Choi, Beom K.;Kwon, Byoung S.
已知激动性抗4-1BB Ab可改善实验性自身免疫性脑脊髓炎。4-1BB触发通常导致产生丰富IFN-γ的CD 8（+）T细胞的扩增，这反过来导致IDO依赖性自身免疫应答的抑制。然而，由于IFN-γ的中和或CD 8（+）T细胞的消耗仅部分消除4-1BB触发的作用，我们试图使用IFN-γ或IFN-γ R缺陷小鼠鉴定4- 1BB触发的自身免疫应答抑制的另外机制。4-1BB触发抑制了负责实验性自身免疫性脑脊髓炎诱导和进展的Th 17细胞的产生，并增加了Foxp 3（+）CD 4（+）调节性T（Treg）细胞，特别是在CD 4（+）T细胞中。这不是由于4-1BB信号对CD 4（+）T细胞分化的直接影响：4-1BB信号不仅减少了野生型小鼠中的Th 17细胞并增加了Treg细胞，这可能是由于CD 8（+）T细胞产生IFN-g，而且在IFN-γ缺陷小鼠中也是如此，在这种情况下，通过下调IL-6的产生。这些结果表明，虽然由4-1BB触发诱发的次级抑制机制通常被IFN-γ的强烈作用掩盖，但4-1BB信号传导似乎通过许多机制调节自身免疫应答，并且调节Th 17与Treg细胞平衡是这些机制之一。免疫学杂志，2011，187：1120-1128。
Agonistic anti-4-1BB Ab is known to ameliorate experimental autoimmune encephalomyelitis. 4-1BB triggering typically leads to the expansion of CD8(+) T cells, which produce abundant IFN-gamma, and this in turn results in IDO-dependent suppression of autoimmune responses. However, because neutralization of IFN-gamma or depletion of CD8(+) T cell only partially abrogates the effect of 4-1BB triggering, we sought to identify an additional mechanism of 4-1BB-triggered suppression of autoimmune responses using IFN-gamma-or IFN-gamma R-deficient mice. 4-1BB triggering inhibited the generation of Th17 cells that is responsible for experimental autoimmune encephalomyelitis induction and progression, and increased Foxp3(+)CD4(+) regulatory T (Treg) cells, particularly among CD4(+) T cells. This was not due to a direct effect of 4-1BB signaling on CD4(+) T cell differentiation: 4-1BB signaling not only reduced Th17 cells and increased Treg cells in wild-type mice, which could be due to IFN-g production by the CD8(+) T cells, but also did so in IFN-gamma-deficient mice, in that case by downregulating IL-6 production. These results show that although secondary suppressive mechanisms evoked by 4-1BB triggering are usually masked by the strong effects of IFN-gamma, 4-1BB signaling seems to modulate autoimmune responses by a number of mechanisms, and modulation of the Th17 versus Treg cell balance is one of those mechanisms. The Journal of Immunology, 2011, 187: 1120-1128.