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

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