IL-17A secretion by CD8+ T cells supports Th17-mediated autoimmune encephalomyelitis
IL-17A secretion by CD8+ T cells supports Th17-mediated autoimmune encephalomyelitis
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DOI：
10.1172/jci63681
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发表时间：
2013-01-01
影响因子：
15.9
通讯作者：
Lohoff, Michael
中科院分区：
文献类型：
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作者：
Huber, Magdalena;Heink, Sylvia;Lohoff, Michael
在多发性硬化（MS）病变中可检测到产生IL-17的CD 8（+）T（Tc 17）细胞;然而，它们对疾病的贡献尚不清楚。为了鉴定Tc 17细胞的功能，我们在缺乏IFN调节因子4（IRF 4）的小鼠中诱导EAE（MS的小鼠模型）。IRF 4缺陷小鼠不能产生Tc 17和Th 17细胞，并且对EAE具有抗性。在这些小鼠中过继转移WT CD 8（+）T细胞并随后免疫诱导EAE后，CD 8（+）T细胞在外周中形成Tc 17表型，但不能浸润CNS。类似地，单独转移少量WT CD 4（+）T细胞不会诱发EAE，但当与CD 8（+）T细胞一起转移时，产生IL-17的CD 4（+）（Th 17）T细胞在CNS中积聚，小鼠发展为严重疾病。Th 17的积累和EAE的发展需要CD 8（+）T细胞产生IL-17 A，这表明Tc 17细胞是促进CD 4（+）T细胞介导的EAE诱导所必需的。因此，早期MS患者脑脊液中的Tc 17细胞数量多于外周血。我们的研究结果表明，Tc 17细胞有助于启动中枢神经系统自身免疫在小鼠和人类通过支持Th 17细胞的致病性。
IL-17-producing CD8(+) T (Tc17) cells are detectible in multiple sclerosis (MS) lesions; however, their contribution to the disease is unknown. To identify functions of Tc17 cells, we induced EAE, a murine model of MS, in mice lacking IFN regulatory factor 4 (IRF4). IRF4-deficient mice failed to generate Tc17 and Th17 cells and were resistant to EAE. After adoptive transfer of WT CD8(+) T cells and subsequent immunization for EAE induction in these mice, the CD8(+) T cells developed a Tc17 phenotype in the periphery but could not infiltrate the CNS. Similarly, transfer of small numbers of WT CD4(+) T cells alone did not evoke EAE, but when transferred together with CD8(+) T cells, IL-17-producing CD4(+) (Th17) T cells accumulated in the CNS and mice developed severe disease. Th17 accumulation and development of EAE required IL-17A production by CD8(+) T cells, suggesting that Tc17 cells are required to promote CD4(+) T cell-mediated induction of EAE. Accordingly, patients with early-stage MS harbored a greater number of Tc17 cells in the cerebrospinal fluid than in peripheral blood. Our results reveal that Tc17 cells contribute to the initiation of CNS autoimmunity in mice and humans by supporting Th17 cell pathogenicity.