GPR15-guided CD8⁺ T regulatory cells control intestinal inflammation.

Abstract

Inflammatory bowel disease (IBD) causes chronic suffering from gastrointestinal inflammation and dysfunction that can progress to colon cancer^1,2. The disease prevalence is increasing and there is an urgent need to better understand its pathogenic mechanisms to improve treatment. We show that GPR15, a G protein-coupled receptor (GPCR) expressed in immune cells and previously described as an entry co-factor for human and simian immunodeficiency viruses³, is a marker and homing receptor for a subset of intramucosal GPR15-guided regulatory CD8⁺ T lymphocytes (CD8⁺ T_IGR). Deleterious GPR15 gene variants in humans cause defective homing of CD8⁺ T_IGR and are associated with severe early-onset IBD. Moreover, CD8⁺ T_IGR cells are reduced in the intestinal mucosa of sporadic IBD patients. In mice, GPR15 deficiency impairs colonic homing of CD8⁺ T_IGR cells, leading to accumulation of inflammatory macrophages and increased susceptibility to colitis. CD8⁺ T_IGR cells potently kill macrophages activated by intestinal damage or disease using Fas ligand (FasL) and TNF-related weak inducer of apoptosis (TWEAK). The identification of CD8⁺ T_IGR cells yields new insights into organ-specific immune regulation and potential therapeutics for IBD.