RORγt expression in Tregs promotes systemic lupus erythematosus via IL‐17 secretion, alteration of Treg phenotype and suppression of Th2 responses

Abstract

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 γt (RORγt). Studies in a model of acute glomerulonephritis unveiled potent regulatory, but also proinflammatory, functions of RORγt+FoxP3+ Tregs. This bi‐functional nature prompted us to suggest the name ‘biTregs’. Importantly, the pathogenic biTreg effects were dependent upon expression of RORγt. We thus aimed to evaluate the contribution of RORγt+FoxP3+ biTregs to pristane‐induced SLE and explored the therapeutic potential of interference with RORγt 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 RORγt 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 RORγt signalling. Finally, and remarkably, biTregs were found to potently suppress anti‐inflammatory Th2 immunity in a RORγt‐dependent manner. Our study thus identifies biTregs as novel players in SLE and advocates RORγt‐directed interventions as promising therapeutic strategies.