Kluger M A, Nosko A, Ramcke T, Goerke B, Meyer M C, Wegscheid C, Luig M, Tiegs G, Stahl R A K, Steinmetz O M
III Medizinische Klinik, Universitätsklinikum Eppendorf, Hamburg, Germany.
Institut für experimentelle Immunologie und Hepatologie, Universitätsklinikum Eppendorf, Hamburg, Germany.
Clin Exp Immunol. 2017 Apr;188(1):63-78. doi: 10.1111/cei.12905. Epub 2017 Jan 5.
Systemic lupus erythematosus (SLE) is a common autoimmune disorder with a complex and poorly understood immunopathogenesis. However, a pathogenic role for the T helper type 17 (Th17) axis was demonstrated by many studies, while regulatory T cells (T ) were shown to mediate protection. Recently, we and others characterized a novel and independent T cell population expressing both the T characteristic transcription factor forkhead box protein 3 (FoxP3) and the Th17-defining retinoic acid receptor-related orphan nuclear receptor γt (RORγt). Studies in a model of acute glomerulonephritis unveiled potent regulatory, but also proinflammatory, functions of RORγt FoxP3 T . This bi-functional nature prompted us to suggest the name 'biT '. Importantly, the pathogenic biT effects were dependent upon expression of RORγt. We thus aimed to evaluate the contribution of RORγt FoxP3 biT to pristane-induced SLE and explored the therapeutic potential of interference with RORγt activation. Our analyses revealed expansion of IL-17 producing biT in a distinctive time-course and organ-specific pattern, coincident with the development of autoimmunity and tissue injury. Importantly, specific ablation of RORγt activation in endogenous biT resulted in significant amelioration of pristane-induced pulmonary vasculitis and lupus nephritis. As potential mechanisms underlying the observed protection, we found that secretion of IL-17 by biT was abrogated completely in FoxP3 × RORC mice. Furthermore, T showed a more activated phenotype after cell-specific inactivation of RORγt signalling. Finally, and remarkably, biT were found to potently suppress anti-inflammatory Th2 immunity in a RORγt-dependent manner. Our study thus identifies biT as novel players in SLE and advocates RORγt-directed interventions as promising therapeutic strategies.
系统性红斑狼疮（SLE）是一种常见的自身免疫性疾病，其免疫发病机制复杂且了解甚少。然而，许多研究证明了辅助性T细胞17（Th17）轴的致病作用，而调节性T细胞（Treg）则显示出介导保护作用。最近，我们和其他人鉴定了一种新的独立T细胞群体，该群体同时表达Treg特征性转录因子叉头框蛋白3（FoxP3）和Th17定义性维甲酸受体相关孤儿核受体γt（RORγt）。在急性肾小球肾炎模型中的研究揭示了RORγt+FoxP3+T细胞具有强大的调节功能，但也具有促炎功能。这种双功能性质促使我们提出“biT细胞”这一名称。重要的是，致病性biT细胞效应依赖于RORγt的表达。因此，我们旨在评估RORγt+FoxP3+biT细胞对 pristane诱导的SLE的作用，并探索干扰RORγt激活的治疗潜力。我们的分析显示，产生IL-17的biT细胞在独特的时间进程和器官特异性模式中扩增，这与自身免疫和组织损伤的发展相一致。重要的是，内源性biT细胞中RORγt激活的特异性消融导致pristane诱导的肺血管炎和狼疮性肾炎得到显著改善。作为观察到的保护作用的潜在机制，我们发现FoxP3×RORC小鼠中biT细胞分泌IL-17的现象完全消失。此外，在细胞特异性失活RORγt信号后，Treg细胞表现出更活化的表型。最后，值得注意的是，发现biT细胞以RORγt依赖的方式有力地抑制抗炎性Th2免疫。因此，我们的研究将biT细胞确定为SLE中的新参与者，并主张将针对RORγt的干预措施作为有前景的治疗策略。
