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

Purpose: 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).

Methods: In this research, an experimental autoimmune uveitis (EAU) mouse model was established to investigate the impact of P2X7R on Th1 and Treg immune responses.

Results: 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.

Conclusions: 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.