GPR15-GPR15L axis controls colon natural TCRαβ cells residency and enteroendocrine cell homeostasis to calibrate metabolism.

GPR15 is a colon homing receptor, but its pattern of expression among gut intestinal intraepithelial lymphocytes and its role on intestinal intraepithelial lymphocyte (IEL) and epithelial homeostasis, as well as systemic metabolism and hormones remain unknown. GPR15L is the only ligand for GPR15 described to date, but whether this is the only functional ligand for GPR15 has not been formally explored. Here we show that GPR15 is expressed by mouse colon IELs, namely natural TCRαβ CD8αα+/- cells. These are reduced in the Gpr15-/- and Gpr15L-/- mice colon intraepithelial compartment. This translates into an overrepresentation of enteroendocrine cells in the colonic epithelium, elevated plasma serotonin and increased insulin secretion in response to local glucose administration. Competitive bone marrow chimeric mice confirm that GPR15L is the only functional colon-expressed chemokine ligand for GPR15. Human GPR15 is expressed and functional, recognizes mouse GPR15L and rescues the phenotypes associated with GPR15 deficiency in our novel GPR15 humanized model, which recapitulates features of the human colon immunobiology more closely than wild type mice. This work extends to the colon and TCRαβ CD8αα T cells the complex natural gut-resident T cell vs intestinal enteroendocrine cells crosstalk that controls systemic hormones and metabolism.