GPR15-Mediated Control of Immune Homeostasis in the Large Intestine

The large intestine is the site most commonly affected in inflammatory bowel disease. Lymphocyte homing, which contributes to inflammation, has been studied extensively in the small intestine, but there is little known about homing to the large intestine. We show here that GPR15, an orphan G-protein coupled receptor known as a SIV/HIV co-receptor, controls the specific homing of T cells, preferentially FOXP3⁺ regulatory T cells (Tregs), to the large intestine lamina propria (LILP). GPR15 expression is modulated by gut microbiota and TGF-β1, but not by retinoic acid or short-chain fatty acids. GPR15-deficient mice had fewer Tregs in LILP and were prone to develop more severe large intestine inflammation, which was rescued by the transfer of GPR15-sufficient Tregs. Our findings thus describe a T cell homing receptor for LILP and indicate that GPR15 plays a key role in mucosal immune homeostasis, largely by regulating the influx of Tregs. Our study also demonstrates that immune tolerance in the gut is functionally compartmentalized through the differential requirements for Treg homing to the small and large bowel.