The role of GPR65 in T cell function and demyelinating autoimmune disease

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that arises due to both environmental and genetic factors. The completion of a large-scale genome wide association study for MS identified many loci, including genes implicated in CD4+ T cell activity. Also uncovered were many uncharacterized or poorly characterized genes with leukocyte restricted expression. These genes are likely to effect T cell activity, given the preponderance of T cell associated genes and the importance of T cells to the progression of MS. The orphan G protein-coupled receptor 65 (GPR65) was identified as a lead candidate. GPR65 is a putative proton sensor on leukocytes. The signaling cascade downstream of receptor activation, how it regulates leukocyte function and its role in autoimmune disease remains unknown.Here, GPR65 is shown to be a novel regulator of T cell function and autoimmune inflammation. Gpr65 deficient mice display no overt phenotype before immunological challenge. However, upon induction of experimental autoimmune encephalomyelitis (EAE), an established model of human MS, Gpr65 deficiency leads to exacerbation of disease. Gpr65 is expressed by most leukocytes including CD4+ T cells and is particularly high on natural killer T (NKT) cells. Analysis of the GPR65 transcriptome in activated CD4+ T cells shows GPR65 signals suppress global cytokine transcription early after activation. In vitro, Gpr65 deficient CD4+ T cells and NKT cells have altered cytokine production in line with a more pathogenic EAE response. Gpr65 deficient myelin-specific CD4+ T cells induce disease in recipients, and display altered cytokine production. The use of CD1d-/- Gpr65 deficient mice also demonstrates an important contribution of NKT cells to elevated disease. These findings show that Gpr65 is an important regulator of T cell activity and that signaling is an important feedback mechanism to inhibit inflammation. This is the first data to demonstrate a role for GPR65 in limiting demyelinating autoimmune disease and points to an important role in MS. As a cell surface receptor, GPR65 represents a highly drugable target; this preliminary work forms the basis for further study into its therapeutic potential. Moreover, as reduced pH is a feature of inflammation, understanding GPR65 signaling illuminates a fundamental immunological process