Rorγt expression in Tregspromotes systemic lupus erythematosus VIA IL-17 secretion, alteration of Tregphenotype 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 Tregcharacteristic 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 biTregeffects were dependent upon expression of RORγt. We thus aimed to evaluate the contribution of RORγt+FoxP3+biTregsto 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 biTregswas abrogated completely in FoxP3Cre× RORCfl/flmice. Furthermore, Tregs showed a more activated phenotype after cell-specific inactivation of RORγt signalling. Finally, and remarkably, biTregswere 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.