Summary
The cytokine receptor IL-23R plays a fundamental role in inflammation and autoimmunity. However, several observations have been difficult to reconcile under the assumption that only Th17 cells critically depend on IL-23 to acquire a pathogenic phenotype. Here, we report that Th1 cells differentiated in vitro with IL-12 + IL-21 show similar levels of IL-23R expression as in pathogenic Th17 cells. We demonstrate that IL-23R is required for Th1 cells to acquire a highly colitogenic phenotype. scRNAseq analysis of intestinal T cells enabled us to identify novel regulators induced by IL-23R-signaling in Th1 cells which differed from those expressed in Th17 cells. The perturbation of one of these regulators (CD160) in Th1 cells inhibited induction of colitis. In this process, we were able to uncouple IL-23R as a purely Th17 cell-specific factor and implicate IL-23R signaling as a pathogenic driver of Th1 cell-mediated tissue inflammation and disease.
Competing Interest Statement
N.Y. is an advisor and/or has equity in Cellarity, Celsius Therapeutics and Rheos Medicines. R.J.X. is cofounder and equity holder in Celsius Therapeutics and Jnana Therapeutics. A.C.A. is a member of the scientific advisory boards for Compass Therapeutics, Tizona Therapeutics, Zumutor Biologics, and ImmuneOncia, which have interests in cancer immunotherapy. A.C.A. and V.K.K. are paid consultants for iTeos Therapeutics. V.K.K. has an ownership interest in and is a member of the scientific advisory board for Tizona Therapeutics. V.K.K. is a co-founder of and has an ownership interest in Celsius Therapeutics. V.K.K. is a co-founder of Bicara therapeutics. A.C.A.'s and V.K.K.'s interests were reviewed and managed by the Brigham and Women's Hospital and Partners Healthcare in accordance with their conflict of interest policies.