Gan Poh-Yi, Fujita Takeshi, Ooi Joshua Daniel, Alikhan Maliha Asghar, Dick Jonathan, Shim Raymond, Odobasic Dragana, O'Sullivan Kim Maree, Kitching Arthur Richard, Holdsworth Stephen Roger
Centre for Inflammatory Diseases, Department of Medicine, Monash Medical Centre, Monash University, Clayton, Victoria 3168, Australia;
Department of Immunology, Monash Health, Monash Medical Centre, Clayton, Victoria 3168, Australia.
J Immunol. 2017 Nov 1;199(9):3042-3050. doi: 10.4049/jimmunol.1602025. Epub 2017 Sep 27.
Myeloperoxidase (MPO) anti-neutrophil cytoplasmic Ab (ANCA)-associated vasculitis results from autoimmunity to MPO. IL-17A plays a critical role in generating this form of autoimmune injury but its cell of origin is uncertain. We addressed the hypothesis that IL-17A-producing γδ T cells are a nonredundant requisite in the development of MPO autoimmunity and glomerulonephritis (GN). We studied MPO-ANCA GN in wild type, αβ, or γδ T cell-deficient (C57BL/6, , and respectively) mice. Both T cell populations played important roles in the generation of autoimmunity to MPO and GN. Humoral autoimmunity was dependent on intact αβ T cells but was unaffected by γδ T cell deletion. Following MPO immunization, activated γδ T cells migrate to draining lymph nodes. Studies in and transfer of γδ T cells to mice show that γδ T cells facilitate the generation of anti-MPO autoimmunity and GN. mice that received γδ T cells demonstrate that the development of anti-MPO autoimmunity and GN are dependent on γδ T cell IL-17A production. Finally, transfer of anti-MPO CD4 T cell clones to naive and wild type mice with planted glomerular MPO shows that γδ T cells are also necessary for recruitment of anti-MPO αβ CD4 effector T cells. This study demonstrates that IL-17A produced by γδ T cells plays a critical role in the pathogenesis of MPO-ANCA GN by promoting the development of MPO-specific αβ T cells.
髓过氧化物酶（MPO）抗中性粒细胞胞浆抗体（ANCA）相关血管炎是由针对MPO的自身免疫引起的。白细胞介素-17A（IL-17A）在这种自身免疫性损伤的发生中起关键作用，但其来源细胞尚不确定。我们探讨了产生IL-17A的γδT细胞在MPO自身免疫和肾小球肾炎（GN）发展中是不可或缺的这一假说。我们研究了野生型、αβ或γδT细胞缺陷（分别为C57BL/6、 和 ）小鼠的MPO-ANCA GN。这两种T细胞群体在针对MPO的自身免疫和GN的发生中都发挥了重要作用。体液自身免疫依赖于完整的αβT细胞，但不受γδT细胞缺失的影响。MPO免疫后，活化的γδT细胞迁移至引流淋巴结。对 小鼠以及将γδT细胞转移至 小鼠的研究表明，γδT细胞促进了抗MPO自身免疫和GN的产生。接受 γδT细胞的 小鼠表明，抗MPO自身免疫和GN的发展依赖于γδT细胞产生IL-17A。最后，将抗MPO CD4 T细胞克隆转移至植入肾小球MPO的幼稚 和野生型小鼠表明，γδT细胞对于募集抗MPOαβCD4效应T细胞也是必需的。这项研究表明，γδT细胞产生的IL-17A通过促进MPO特异性αβT细胞的发育，在MPO-ANCA GN的发病机制中起关键作用。
