Oral Presentation Australasian Society for Immunology Annual Scientific Meeting 2014

Gpr65 deficiency exacerbates experimental autoimmune encephalomyelitis, altering CD4+ helper T cell and NKT cell cytokine production (#123)

Rushika Wirasinha 1 2 , Dipti Vijayan 1 2 , Grant Parnell 3 , Kylie Webster 1 2 , Cecile King 1 2 , Robert Brink 1 2 , David Booth 3 , Marcel Batten 1 2
  1. Garvan Institute, Darlinghurst, NSW, Australia
  2. St. Vincent's Clinical School, UNSW Australia, Sydney, NSW, Australia
  3. Westmead Millenium Institute, University of Sydney, Sydney, NSW, Australia

Multiple sclerosis (MS) is a demyelinating disease of the CNS that arises due to environmental and genetic factors. A large-scale MS genome wide association study identified 110 loci, including the G-protein coupled receptor 65 (GPR65) locus. This gene encodes an acid sensing GPCR that is exclusively expressed in hematopoietic cells. Local acidosis is a feature of inflammation, and thus understanding the effect of GPR65 signaling on the regulation of immune function will illuminate a fundamental immunological process as well as its role in autoimmune disease.

We have found that Gpr65 deficient mice develop exacerbated disease in the EAE model of MS. Gpr65 is expressed by most leukocytes, including CD4+ helper T cells, which are central to disease progression. It is also expressed at particularly high levels by NKT cells. In vitro stimulation experiments indicate that Gpr65 deficient CD4+ T cells and NKT cells have altered cytokine production, in line with a more pathogenic EAE response. Using CD1d-/-Gpr65 deficient mice, we demonstrate that NKT cells contribute to elevated disease. Additionally, the passive transfer of Gpr65 deficient MOG35-55-specific CD4+ T cells altered cytokine production in the recipients and induced exacerbated disease, suggesting Gpr65 signals to conventional CD4+ cells also contribute to its effect.

Thus Gpr65 appears to be an important regulator of conventional and innate-like T cell activity during inflammation. Understanding the role of this cell surface receptor may give rise to novel therapeutic strategies for the treatment of MS and other inflammatory conditions.