ROR[gamma]t expression in Tregs promotes systemic lupus erythematosus via IL-17 secretion, alteration of Treg phenotype and suppression of Th2 responses

• Published in: Clinical and experimental immunology 2017-04, Vol.188 (1), p.63
• Main Authors: 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
• Format: Article
• Language: English
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1111/cei.12905

Summary 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 (Tregs) were shown to mediate protection. Recently, we and others characterized a novel and independent T cell population expressing both the Treg characteristic transcription factor forkhead box protein 3 (FoxP3) and the Th17-defining retinoic acid receptor-related orphan nuclear receptor [gamma]t (ROR[gamma]t). Studies in a model of acute glomerulonephritis unveiled potent regulatory, but also proinflammatory, functions of ROR[gamma]t+FoxP3+ Tregs. This bi-functional nature prompted us to suggest the name 'biTregs'. Importantly, the pathogenic biTreg effects were dependent upon expression of ROR[gamma]t. We thus aimed to evaluate the contribution of ROR[gamma]t+FoxP3+ biTregs to pristane-induced SLE and explored the therapeutic potential of interference with ROR[gamma]t activation. Our analyses revealed expansion of IL-17 producing biTregs in a distinctive time-course and organ-specific pattern, coincident with the development of autoimmunity and tissue injury. Importantly, specific ablation of ROR[gamma]t activation in endogenous biTregs 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 biTregs was abrogated completely in FoxP3Cre × RORCfl/fl mice. Furthermore, Tregs showed a more activated phenotype after cell-specific inactivation of ROR[gamma]t signalling. Finally, and remarkably, biTregs were found to potently suppress anti-inflammatory Th2 immunity in a ROR[gamma]t-dependent manner. Our study thus identifies biTregs as novel players in SLE and advocates ROR[gamma]t-directed interventions as promising therapeutic strategies.