RORγt phosphorylation protects against T cell-mediated inflammation

  • Cell Rep. 2022 Mar 15;38(11):110520. doi: 10.1016/j.celrep.2022.110520.
Shengyun Ma  1 ,  Shefali A Patel  2 ,  Yohei Abe  1 ,  Nicholas Chen  1 ,  Parth R Patel  1 ,  Benjamin S Cho  1 ,  Nazia Abbasi  1 ,  Suling Zeng  3 ,  Bernd Schnabl  3 ,  John T Chang  3 ,  Wendy Jia Men Huang  4
Affiliations
  • 1. Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
  • 2. Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
  • 3. Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Medicine, Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA.
  • 4. Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. Electronic address: [email protected].
PMID: 35294872 DOI: 10.1016/j.celrep.2022.110520
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 RORγtS182A knockin mice experience exacerbated inflammation in models of colitis and experimental autoimmune encephalomyelitis (EAE). In summary, the IL-1β-ERK-RORγtS182 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.
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