| First Author | Kluger MA | Year | 2017 |
| Journal | Clin Exp Immunol | Volume | 188 |
| Issue | 1 | Pages | 63-78 |
| PubMed ID | 27880975 | Mgi Jnum | J:312605 |
| Mgi Id | MGI:6792031 | Doi | 10.1111/cei.12905 |
| Citation | Kluger MA, et al. (2017) RORgammat expression in Tregs promotes systemic lupus erythematosus via IL-17 secretion, alteration of Treg phenotype and suppression of Th2 responses. Clin Exp Immunol 188(1):63-78 |
| abstractText | 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 gammat (RORgammat). Studies in a model of acute glomerulonephritis unveiled potent regulatory, but also proinflammatory, functions of RORgammat(+) FoxP3(+) Tregs . This bi-functional nature prompted us to suggest the name 'biTregs '. Importantly, the pathogenic biTreg effects were dependent upon expression of RORgammat. We thus aimed to evaluate the contribution of RORgammat(+) FoxP3(+) biTregs to pristane-induced SLE and explored the therapeutic potential of interference with RORgammat 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 RORgammat 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 FoxP3(Cre) x RORC(fl/fl) mice. Furthermore, Tregs showed a more activated phenotype after cell-specific inactivation of RORgammat signalling. Finally, and remarkably, biTregs were found to potently suppress anti-inflammatory Th2 immunity in a RORgammat-dependent manner. Our study thus identifies biTregs as novel players in SLE and advocates RORgammat-directed interventions as promising therapeutic strategies. |
