GPR15 (G protein-coupled receptor 15) functions as a critical T cell homing receptor that regulates immune cell trafficking, particularly to intestinal tissues. GPR15 acts as a chemokine receptor that controls the migration of regulatory T cells (Tregs) and cytotoxic T cells to the colon, with its natural ligand C10orf99 establishing a novel signaling axis for intestinal homeostasis 1. The receptor operates upstream of α4β7 and α4β1 integrins, controlling T cell adhesion to MAdCAM-1 and VCAM-1 2. GPR15 expression is strongly influenced by environmental factors, particularly smoking and dietary L-tryptophan consumption. Smoking significantly upregulates GPR15 expression through aryl hydrocarbon receptor (AhR) activation 3, while dietary L-tryptophan is converted by host IDO1/2 enzymes to compounds that induce GPR15 transcription preferentially in Tregs 4. Functionally, GPR15-mediated T cell recruitment facilitates viral elimination during myocarditis 5 and plays opposing roles in inflammatory bowel diseases - worsening Crohn's disease while protecting against ulcerative colitis through differential effects on Th17 and Treg cell populations 6. These findings establish GPR15 as a promising therapeutic target for inflammatory conditions, with anti-GPR15 antibodies effectively blocking T cell gut homing in experimental models 2.