Innate IFN-γ promotes development of experimental autoimmune encephalomyelitis: A role for NK cells and M1 macrophages
Innate IFN-γ promotes development of experimental autoimmune encephalomyelitis: A role for NK cells and M1 macrophages
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DOI：
10.1002/eji.201444612
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发表时间：
2014-10-01
影响因子：
5.4
通讯作者：
Mills, Kingston H. G.
中科院分区：
文献类型：
--
作者：
Dungan, Lara S.;McGuinness, Niamh C.;Mills, Kingston H. G.
IFN-γ在自身免疫性疾病发病机制中的作用是有争议的。虽然Th 1细胞可以诱导实验性自身免疫性脑脊髓炎（EAE），但IFN-γ可以抑制在EAE中致病的Th 17细胞。在这里，我们表明，NK细胞提供了早期来源的IFN-γ在发展的EAE。NK细胞的耗竭或IFN-γ的中和延迟了EAE的发作，并且与IL-17+和GM-CSF+ T细胞向CNS的浸润减少相关。在被动转移模型中，来自髓鞘少突胶质细胞糖蛋白（MOG）免疫的IFN-γ（-/-）小鼠的免疫细胞尽管产生IL-17和GM-CSF，但未能诱导EAE。巨噬细胞表达M2活化标志物，T细胞极晚期抗原-4（VLA-4）表达较低，无法浸润CNS。将重组IFN-γ添加到来自IFN-γ（-/-）小鼠的免疫细胞中激活M1巨噬细胞并恢复T细胞的VLA-4表达、迁移和致脑炎活性。此外，用抗VLA-4中和抗体治疗受体小鼠消除了由来自WT小鼠的T细胞转移诱导的EAE。我们的研究结果表明产生IFN-γ的T细胞不是EAE发展所必需的，但NK细胞衍生的IFN-γ在促进M1巨噬细胞扩增和VLA-4介导的致脑炎T细胞迁移到CNS中具有关键作用。
The role of IFN-gamma in the pathogenesis of autoimmune diseases is controversial. Although Th1 cells can induce experimental autoimmune encephalomyelitis (EAE), IFN-gamma can suppress Th17 cells that are pathogenic in EAE. Here we show that NK cells provide an early source of IFN-gamma during development of EAE. Depletion of NK cells or neutralization of IFN-gamma delayed the onset of EAE and was associated with reduced infiltration of IL-17+ and GM-CSF+ T cells into the CNS. In the passive transfer model, immune cells from myelin oligodendrocyte glycoprotein (MOG)-immunized IFN-gamma(-/-) mice failed to induce EAE, despite producing IL-17 and GM-CSF. The macrophages expressed markers of M2 activation and the T cells had low very late antigen-4 (VLA-4) expression and failed to infiltrate the CNS. Addition of recombinant IFN-gamma to immune cells from the IFN-gamma(-/-) mice activated M1 macrophages and restored VLA-4 expression, migratory, and encephalitogenic activity of T cells. Furthermore, treatment of recipient mice with anti-VLA-4 neutralizing antibody abrogated EAE induced by transfer of T cells from WT mice. Our findings demonstrate IFN-gamma-producing T cells are not required for development of EAE, but NK cell-derived IFN-gamma has a key role in promoting M1 macrophage expansion and VLA-4-mediated migration of encephalitogenic T cells into the CNS.