Research ArticleImmunology

A natural ligand for the orphan receptor GPR15 modulates lymphocyte recruitment to epithelia

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Science Signaling  12 Sep 2017:
Vol. 10, Issue 496, eaal0180
DOI: 10.1126/scisignal.aal0180

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Deorphanizing a chemoattractant receptor

The orphan G protein–coupled receptor GPR15 mediates the trafficking of lymphocytes to the colon and the skin and the recruitment of effector T cells to inflamed intestinal tissue. Suply et al. purified a natural ligand of GPR15 (GPR15L) from porcine colonic extracts. In vitro assays showed that GPR15L specifically activated GPR15, but not other chemoattractant receptors. Although migration assays suggested that GPR15L inhibited chemokine-induced T cell migration, mouse skin allotransplantations showed that GPR15L recruited CD8+ T cells to the graft and that loss of the ligand was associated with increased graft protection. Given that GPR15L mRNA is abundant in psoriatic lesions, these data suggest that targeting the GPR15-GPR15L axis may help in the treatment of inflammatory skin conditions.


GPR15 is an orphan G protein–coupled receptor (GPCR) that is found in lymphocytes. It functions as a co-receptor of simian immunodeficiency virus and HIV-2 and plays a role in the trafficking of T cells to the lamina propria in the colon and to the skin. We describe the purification from porcine colonic tissue extracts of an agonistic ligand for GPR15 and its functional characterization. In humans, this ligand, which we named GPR15L, is encoded by the gene C10ORF99 and has some features similar to the CC family of chemokines. GPR15L was found in some human and mouse epithelia exposed to the environment, such as the colon and skin. In humans, GPR15L was also abundant in the cervix. In skin, GPR15L was readily detected after immunologic challenge and in human disease, for example, in psoriatic lesions. Allotransplantation of skin from Gpr15l-deficient mice onto wild-type mice resulted in substantial graft protection, suggesting nonredundant roles for GPR15 and GPR15L in the generation of effector T cell responses. Together, these data identify a receptor-ligand pair that is required for immune homeostasis at epithelia and whose modulation may represent an alternative approach to treating conditions affecting the skin such as psoriasis.

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