P2Y2R Deficiency Attenuates Experimental Autoimmune Uveitis Development

We aimed to study the role of the nucleotide receptor P2Y(2)R in the development of experimental autoimmune uveitis (EAU). EAU was induced in P2Y(2)(+/+) and P2Y(2)(-/-) mice by immunization with IRBP peptide or by adoptive transfer of in vitro restimulated semi-purified IRBP-specific enriched T lymphocytes from spleens and lymph nodes isolated from native C57BI/6 or P2Y(2)(+/+) and P2Y(2)(-/-) immunized mice. Clinical and histological scores were used to grade disease severity. Splenocytes and lymph node cell phenotypes were analyzed using flow cytometry. Semi-purified lymphocytes and MACS-purified CD4(+) T lymphocytes from P2Y(2)(+/+) and P2Y(2)(-/-) immunized mice were tested for proliferation and cytokine secretion. Our data show that clinical and histological scores were significantly decreased in IRBP-immunized P2Y(2)(-/-) mice as in P2Y(2)(-/-) mice adoptively transfered with enriched T lymphocytes from C57BI/6 IRBP-immunized mice. In parallel, naive C57BI/6 mice adoptively transferred with T lymphocytes from P2Y(2)(-/-) IRBP-immunized mice also showed significantly less disease. No differences in term of spleen and lymph node cell recruitment or phenotype appeared between P2Y(2)(-/-) and P2Y(2)(+/+) immunized mice. However, once restimulated in vitro with IRBP, P2Y(2)(-/-) T cells proliferate less and secrete less cytokines than the P2Y(2)(+/+) one. We further found that antigen-presenting cells of P2Y(2)(-/-) immunized mice were responsible for this proliferation defect. Together our data show that P2Y(2)(-/-) mice are less susceptible to mount an autoimmune response against IRBP. Those results are in accordance with the danger model, which makes a link between autoreactive lymphocyte activation, cell migration and the release of danger signals such as extracellular nucleotides.