Human GPR15 deficiency reveals CD8+ T regulatory cell-macrophage crosstalk in intestinal inflammation

We employed a CITE-seq combined with single-cell sequencing approach using 10x Genomics scRNA-seq to analyze peripheral and intestinal lymphocytes from Gpr15⁻/⁻ mice and from patients carrying deleterious GPR15 mutations. 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, serves as a crucial marker and homing receptor for a unique subset of intramucosal GPR15-guided regulatory CD8⁺ T lymphocytes (CD8⁺ TIGR cells). Our results demonstrate that deleterious GPR15 variants in humans impair the homing of CD8⁺ TIGR cells, leading to severe early-onset inflammatory bowel disease (IBD). In mice, GPR15 deficiency disrupts the colonic recruitment of CD8⁺ TIGR cells, causing an accumulation of inflammatory macrophages and heightened susceptibility to colitis. Together, our findings identify CD8⁺ TIGR cells as a previously unrecognized component of organ-specific immune regulation and reveal potential therapeutic avenues for the treatment of IBD.