GPR15-guided CD8T regulatory cells control intestinal inflammation.

Source: PubMed, NCBI / U.S. National Library of Medicine

Inflammatory bowel disease (IBD) causes chronic suffering from gastrointestinal inflammation and dysfunction that can progress to colon cancer. 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 viruses, is a marker and homing receptor for a subset of intramucosal GPR15-guided regulatory CD8T lymphocytes (CD8T). Deleterious GPR15 gene variants in humans cause defective homing of CD8Tand are associated with severe early-onset IBD. Moreover, CD8Tcells are reduced in the intestinal mucosa of sporadic IBD patients. In mice, GPR15 deficiency impairs colonic homing of CD8Tcells, leading to accumulation of inflammatory macrophages and increased susceptibility to colitis. CD8Tcells potently kill macrophages activated by intestinal damage or disease using Fas ligand (FasL) and TNF-related weak inducer of apoptosis (TWEAK). The identification of CD8Tcells yields new insights into organ-specific immune regulation and potential therapeutics for IBD.