Identification of the Orphan Receptor GPR15 as a Potential Gut Homing Receptor on Human CD4 T Cells

Immune responses in the intestine are tightly regulated to ensure host protective immunity in the absence of immune pathology. A permanent disturbance of this delicate balance can lead to the development of inflammatory bowel disease (IBD). Additionally, there is compelling evidence that dysregulated effector CD4 T cells accumulate in the inflamed intestine and contribute to the chronicity of disease.

Homing of CD4 T cells to the intestine is thought to be a vital process in disease initiation and progression. G-protein coupled receptors guide lymphocytes towards the site of inflammation, including the G-protein coupled orphan receptor GPR15. This receptor has been recently described to regulate homing of mouse regulatory and effector CD4 T cells to the large intestine.

Here we characterized the expression pattern of GPR15 and its putative role in regulating human T cell homing to the gastrointestinal tract. In healthy individuals and IBD patients, GPR15 was expressed on memory CD4 T cells in combination with several chemokine receptors regulating lymphocyte migration towards the gastrointestinal tract and the skin. GPR15+ memory T cells were identified within circulating as well as tissue resident lymphocytes. GPR15 expression marked a unique subset of gut-homing CD4 T cells and was independent of integrin α4β7 and CCR9 expression. GPR15+ CD4 T cells produced the cytokines IFNγ, IL-22 and IL-17A. Finally, GPR15 expression was altered in mucosal tissue of Crohn's disease patients.

Taken together, our findings provide new evidence to a putative tissue homing receptor, which regulates the migration of memory CD4 T cells to gut and skin.