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 γt (RORγt). Studies in a model of acute glomerulonephritis unveiled potent regulatory, but also proinflammatory, functions of RORγt⁺ 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 RORγt. We thus aimed to evaluate the contribution of RORγt⁺ FoxP3⁺ biT_regs to pristane-induced SLE and explored the therapeutic potential of interference with RORγt 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 RORγt 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 × RORC^fl/fl mice. Furthermore, T_regs showed a more activated phenotype after cell-specific inactivation of RORγt signalling. Finally, and remarkably, biT_regs were found to potently suppress anti-inflammatory Th2 immunity in a RORγt-dependent manner. Our study thus identifies biT_regs as novel players in SLE and advocates RORγt-directed interventions as promising therapeutic strategies.

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