Introduction and Background: Lymphocytes are key mediators of inflammation and IBD, including ulcerative colitis (UC). GPR15 is a chemoattractant receptor for lymphocyte homing to the colon and is implicated in mouse models of colitis. It is expressed by subsets of CD4 and CD8 effector and of CD4 regulatory T cells in both human and mouse. In humans the receptor is highly expressed by presumed pathogenic Th2 cells in the colonic lamina propria of UC patients. In mice it is expressed by colon-homing pathogenic Th17 cells, and deficiency of GPR15 suppresses colitis in the naïve T cell transfer model. Thus GPR15 is considered as a promising target to control the recruitment of pathogenic effector T cells to the colon. The pursuit of the receptor as a drug target has been hampered by the lack of understanding of its physiological ligand. Recently, in an exploratory study included in a patent filed by Novartis, the 9 kDa CC-motif containing cationic polypeptide AP57/colon-derived SUSD2 binding factor (CSBF), encoded by C10orf99 in the human and 2610528A11Rik in the mouse, was reported to trigger Ca2+-mediated signaling upon interaction with GPR15. Aim: To describe AP57 as the colon-expressed chemokine ligand for GPR15 (GPR15L). Methods: In vitro assays of GPR15 activation (beta arrestin) by GPR15L, competitive GPR15L binding of GPR15 and GPR15L-driven chemotactic migration (Transwell). Results: GPR15L binds and activates GPR15, as well as attracts in a GPR15-dependent manner GPR15-expressing T cells including lymphocytes in colon draining lymph nodes and Vγ3+ thymic precursors of dermal epithelial T cells. Conclusion: Identification of the chemotactic activity of GPR15L, and its characterization as the colon-expressed chemotactic ligand for GPR15, adds to its already reported anti-bacterial activities, and suggests the potential of targeting GPR15L-GPR15 interactions for the development of new drugs intended to improve the clinical management of UC.
