IFN-γ and IL-17 production in experimental autoimmune encephalomyelitis depends on local APC-T cell complement production
IFN-γ and IL-17 production in experimental autoimmune encephalomyelitis depends on local APC-T cell complement production
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DOI：
10.4049/jimmunol.180.9.5882
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发表时间：
2008-05-01
影响因子：
4.4
通讯作者：
Medof, M. Edward
中科院分区：
文献类型：
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作者：
Liu, Jinbo;Lin, Feng;Medof, M. Edward
产生干扰素-γ和白介素17的T细胞跨髓鞘成分的自身反应是多发性硬化症发病机制的核心。利用体内直接转移、过继转移和体外系统，本研究表明，在髓鞘少突胶质细胞糖蛋白(35-55)诱导的实验性自身免疫性脑脊髓炎中，这些效应物的产生依赖于局部产生的C3a/C5a与APC和T细胞C3aR/C5aR的相互作用。在没有细胞表面C3/C5转化酶抑制因子(DAF)的情况下，但在APC和T细胞上没有DAF和C5aR和/或C3aR的联合缺乏时，发生了高度的局部自身免疫反应，其中髓鞘破坏显著增加，同时显著增加了干扰素-γ(+)和IL-17(+)T细胞的产生。增强的T细胞反应是由于APC增加了IL-12和IL-23的分泌，以及每种细胞因子受体的T细胞表达增加。这些结果适用于IL-17表型的初始生成，因为幼稚的CD62L(高)Daf1(-/-)T细胞对转化生长因子-β和IL-6的反应产生更多的IL-17，而CD62L高的Daf1(-/-)C5aR(-/-)C3aR(-/-)细胞产生的IL-17要少4倍。
IFN-gamma- and IL-17-producing T cells autoreactive across myelin components are central to the pathogenesis of multiple sclerosis. Using direct in vivo, adoptive transfer, and in vitro systems, we show in this study that the generation of these effectors in myelin oligodendrocyte glycoprotein(35-55)-induced experimental autoimmune encephalomyelitis depends on interactions of locally produced C3a/C5a with APC and T cell C3aR/C5aR. In the absence of the cell surface C3/C5 convertase inhibitor decay-accelerating factor (DAF), but not the combined absence of DAF and C5aR and/or C3aR on APC and T cells, a heightened local autoimmune response occurs in which myelin destruction is markedly augmented in concert with markedly more IFN-gamma(+) and IL-17(+) T cell generation. The augmented T cell response is due to increased IL-12 and IL-23 elaboration by APCs together with increased T cell expression of the receptors for each cytokine. The results apply to initial generation of the IL-17 phenotype because naive CD62L(high)Daf1(-/-) T cells produce Mold more IL-17 in response to TGF-beta and IL-6, whereas CD62L high Daf1(-/-)C5aR(-/-)C3aR(-/-) cells produce 4-fold less.