Rus Violeta, Nguyen Vinh, Tatomir Alexandru, Lees Jason R, Mekala Armugam P, Boodhoo Dallas, Tegla Cosmin A, Luzina Irina G, Antony Paul A, Cudrici Cornelia D, Badea Tudor C, Rus Horea G
Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201;
Research Service, Veteran Affairs Medical Center, Baltimore, MD 21201.
J Immunol. 2017 May 15;198(10):3869-3877. doi: 10.4049/jimmunol.1602158. Epub 2017 Mar 29.
Th17 cells play a critical role in autoimmune diseases, including multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Response gene to complement (RGC)-32 is a cell cycle regulator and a downstream target of TGF-β that mediates its profibrotic activity. In this study, we report that RGC-32 is preferentially upregulated during Th17 cell differentiation. RGC-32 mice have normal Th1, Th2, and regulatory T cell differentiation but show defective Th17 differentiation in vitro. The impaired Th17 differentiation is associated with defects in IFN regulatory factor 4, B cell-activating transcription factor, retinoic acid-related orphan receptor γt, and SMAD2 activation. In vivo, RGC-32 mice display an attenuated experimental autoimmune encephalomyelitis phenotype accompanied by decreased CNS inflammation and reduced frequency of IL-17- and GM-CSF-producing CD4 T cells. Collectively, our results identify RGC-32 as a novel regulator of Th17 cell differentiation in vitro and in vivo and suggest that RGC-32 is a potential therapeutic target in multiple sclerosis and other Th17-mediated autoimmune diseases.
辅助性T细胞17（Th17细胞）在自身免疫性疾病中发挥关键作用，包括多发性硬化症及其动物模型实验性自身免疫性脑脊髓炎。补体反应基因（RGC）-32是一种细胞周期调节因子，也是转化生长因子-β（TGF-β）的下游靶点，介导其促纤维化活性。在本研究中，我们报告RGC-32在Th17细胞分化过程中优先上调。RGC-32基因敲除小鼠的Th1、Th2和调节性T细胞分化正常，但在体外表现出Th17分化缺陷。Th17分化受损与干扰素调节因子4、B细胞活化转录因子、维甲酸相关孤儿受体γt和SMAD2激活缺陷有关。在体内，RGC-32基因敲除小鼠表现出实验性自身免疫性脑脊髓炎表型减弱，伴有中枢神经系统炎症减轻以及产生白细胞介素-17和粒细胞-巨噬细胞集落刺激因子的CD4 T细胞频率降低。总体而言，我们的结果确定RGC-32是体外和体内Th17细胞分化的新型调节因子，并表明RGC-32是多发性硬化症和其他Th17介导的自身免疫性疾病的潜在治疗靶点。
