Induction of a colitogenic phenotype in Th1-like cells depends on interleukin-23 receptor signaling

• DOI: 10.1016/j.immuni.2022.08.007
• Publication Date: 2022-09-06T15:21:34Z
• Authors: Mathias Pawlak; David DeTomaso; Alexandra Schnell; Gerd Meyer zu Horste; Youjin Lee; Jackson Nyman; Danielle Dionne; Brianna M.L. Regan; Vasundhara Singh; Toni Delorey; Markus A. Schramm; Chao Wang; Antonia Wallrapp; Patrick R. Burkett; Samantha J. Riese...; Ana C. Anderson; Aviv Regev; Ramnik J. Xavier; Nir Yosef; Vijay K. Kuchroo
• Keywords: Inflammation; Receptors, Interleukin; Th1 Cells; Colitis; Interleukin-23; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Phenotype; 0302 clinical medicine; Animals; Th17 Cells

Interleukin-23 receptor plays a critical role in inducing inflammation and autoimmunity. Here, we report that Th1-like cells differentiated in vitro with IL-12 + IL-21 showed similar IL-23R expression to that of pathogenic Th17 cells using eGFP reporter mice. Fate mapping established that these cells did not transition through a Th17 cell state prior to becoming Th1-like cells, and we observed their emergence in vivo in the T cell adoptive transfer colitis model. Using IL-23R-deficient Th1-like cells, we demonstrated that IL-23R was required for the development of a highly colitogenic phenotype. Single-cell RNA sequencing analysis of intestinal T cells identified IL-23R-dependent genes in Th1-like cells that differed from those expressed in Th17 cells. The perturbation of one of these regulators (CD160) in Th1-like cells inhibited the induction of colitis. We thus uncouple IL-23R as a purely Th17 cell-specific factor and implicate IL-23R signaling as a pathogenic driver in Th1-like cells inducing tissue inflammation.