Human G Protein-Coupled Receptor 15 mutations associated with inflammatory bowel disease.

Abstract

Abstract G Protein-Coupled Receptor 15 (GPR15) is a chemokine receptor, primarily expressed in T cells based on human single-cell RNA sequencing data. Its natural ligand, GPR15L, is found in the gastrointestinal basal epithelial region and presumably guide GPR15+ T cells to that location. Previous studies showed that Gpr15−/− mice were more susceptible to C. rodentium-induced colitis but the function of GPR15 and whether its deficiency plays a role in inflammatory bowel disease (IBD) in humans are unclear. We recruited three pediatric patients who developed severe early onset IBD and found novel GPR15 mutations using whole-exome sequencing. A reduction in T cells was observed in patient colon biopsies. Surface staining of patient T cells after TCR stimulation further revealed low expression of the mutant GPR15 alleles compared to the wildtype. Characterizing the GPR15 mutants in transduced stable cell lines, we found that the mutations led to lower GPR15L-dependent signaling, causing decreased cell chemotaxis towards the ligand. Accordingly, Gpr15−/− mouse colon also exhibited reduced T cell phenotype observed in patients. Our results indicate that GPR15 is critical for T cell and migration to the human colon and its absence may lead to immunodeficiency in the region, predisposing individuals to IBD induced by specific pathogenic microbiota. This research was supported NIAID by the Intramural Research Program of the NIH. This research was supported NIAID by the Intramural Research Program of the NIH.