GPR15-guided CD8⁺ T regulatory cells control intestinal inflammation

Inflammatory bowel disease (IBD) causes chronic suffering from gastrointestinal inflammation and dysfunction that can progress to colon cancer1,2. 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 i ntramucosal G PR15-guided r egulatory 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.