Reverse Regulation of Th1 and Treg Immune Responses by P2X7 Receptor: A Possible Cause of the Progression of Experimental Autoimmune Uveitis

To study the regulatory effects and mechanisms of P2X7 receptors(P2X7R) on CD4+ regulatory T cells (Tregs) and pathogenic CD4+ T effector cells (Th1 cells). In this research, an experimental autoimmune uveitis (EAU) mouse model was established to investigate the impact of P2X7R on Th1 and Treg immune responses. During the initial stage of EAU, appropriate activation of P2X7R leads to an enhanced Th1 immune response, including an increased proportion of CD4+ IFN-γ+ Th1 cells, increased production of cytokines tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), and upregulation of transcription factor T-bet expression. Conversely, activation of P2X7R resulted in inhibition of Treg immune response, including a reduced proportion of CD4+Foxp3+Tregs, a decreased in cytokines transforming growth factor-beta (TGF-β) and interleukin-10 (IL-10), and a downregulation of the transcription factor Foxp3 expression. Extracellular signal-regulated kinase 1/2 (ERK1/2) signal and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) may be related to these effects. Interestingly, we observed that both Th1 and Tregs immune responses were reduced in P2rx-/- mice compared with P2rx7+/+ mice. Our findings indicate that the promoting role of P2X7R in the early pathogenesis of EAU may be related to the contrary regulation of Th1 cells and Tregs, providing a new theoretical basis for the development of P2X7R targeted therapy.