Role and species-specific expression of colon T cell homing receptor GPR15 in colitis

The chemoattractant receptor GPR15 can direct CD4 + T cells to the colon. Habtezion and colleagues show that GATA-3 and Foxp3 exhibit species-specific differences in promoting GPR15 expression and thereby influences homing of CD4 + effector and regulatory T cells. Lymphocyte recruitment maintains intestinal immune homeostasis but also contributes to inflammation. The orphan chemoattractant receptor GPR15 mediates regulatory T cell homing and immunosuppression in the mouse colon. We show that GPR15 is also expressed by mouse T H 17 and T H 1 effector cells and is required for colitis in a model that depends on the trafficking of these cells to the colon. In humans GPR15 is expressed by effector cells, including pathogenic T H 2 cells in ulcerative colitis, but is expressed poorly or not at all by colon regulatory T (T reg ) cells. The T H 2 transcriptional activator GATA-3 and the T reg -associated transcriptional repressor FOXP3 robustly bind human, but not mouse, GPR15 enhancer sequences, correlating with receptor expression. Our results highlight species differences in GPR15 regulation and suggest it as a potential therapeutic target for colitis.