Crucial role of P2X₇ receptor for effector T cell activation in experimental autoimmune uveitis

Purpose: To investigate the roles of P2X7 receptors (P2RX7) in the pathogenesis of experimental autoimmune uveoretinitis (EAU). Study design: Experimental. Methods: Either wild-type (P2rx7^+/+) or P2rx7-deficient (P2rx7) mice were immunized with interphotoreceptor retinoid-binding protein (IRBP) peptide 1-20. Severity of EAU was evaluated clinically and histopathologically. The induction of IRBP-specific proliferation and cytokines in draining lymph nodes was assessed by enzyme-linked immunosorbent assays (ELISA). The frequency of activation markers was examined by flow cytometry. Furthermore, inhibitory roles of systemic administration of Brilliant Blue G (BBG), an antagonist for P2RX7, in EAU were also assessed in the wild-type mice. Results: The severity of EAU in P2rx7 mice was reduced as compared with that in P2rx7^+/+ mice, both clinically and histopathologically. IRBP-specific proliferation in P2rx7 on day 16 was slightly decreased compared to that in P2rx7^+/+ mice. The induction of IRBP-specific interferon (IFN)-γ and interleukin (IL)-17 in P2rx7 mice on day 16 was lower than that in P2rx7^+/+ mice. The up-regulation of surface expression of activation markers such as CD25, CD44, and CD69 in response to TCR stimulation in P2rx7 mice was decreased as compared with that in P2rx7^+/+ mice. Furthermore, neutralization of P2RX7 in vivo by BBG suppressed EAU clinically and histopathologically. IRBP-specific IFN-γ and IL-17 induction in BBG-treated mice was significantly lower than that in vehicle-treated mice. Conclusion: The results suggest that P2RX7 is a novel preventative therapeutic target for uveitis as it suppresses the effector functions of both Th1 and Th17 cell responses.