RORγt phosphorylation protects against T cell-mediated inflammation

Abstract

RAR-related orphan receptor-γ (RORγt) is an essential transcription factor for thymic T cell development, secondary lymphoid tissue organogenesis, and peripheral immune cell differentiation. Serine 182 phosphorylation is a major post-translational modification (PTM) on RORγt. However, the in vivo contribution of this PTM in health and disease settings is unclear. We report that this PTM is not involved in thymic T cell development and effector T cell differentiation. Instead, it is a critical regulator of inflammation downstream of IL-1β signaling and extracellular signal regulated kinases (ERKs) activation. ERKs phosphorylation of serine 182 on RORγt serves to simultaneously restrict Th17 hyperactivation and promote anti-inflammatory cytokine IL-10 production in RORγt⁺ Treg cells. Phospho-null RORγt^S182A knockin mice experience exacerbated inflammation in models of colitis and experimental autoimmune encephalomyelitis (EAE). In summary, the IL-1β-ERK-RORγt^S182 circuit protects against T cell-mediated inflammation and provides potential therapeutic targets to combat autoimmune diseases.

Keywords: EAE; ERK; IL-10; IL-17A; RORγt; RORγt(+) Tregs; Th17; colitis; inflammation; phosphorylation.