TGF beta mediates crosstalk between CD8 Positive T cells and CD39 Positive induced Treg cells in autoimmune inflammation
Autoimmune inflammation results from dysregulated immune responses, in which dysfunction of regulatory T cells (Tregs) is recognized as a key contributing factor due to their essential role in maintaining immune homeostasis and preventing autoimmunity. The stability and functionality of Tregs are heavily influenced by their immune microenvironment, including inflammatory and tumor contexts. Tregs comprise diverse subsets, but the distinctions and interactions among these populations remain poorly understood. Although CD8+ T cells have been implicated in autoimmune disease pathogenesis, their interactions with CD4+ Foxp3+ Tregs and the underlying regulatory mechanisms are not well characterized. In this study, we identified CD8+ T cells as crucial enhancers of CD4+ induced Treg (iTreg) differentiation, function, and stability. CD8+ T cells markedly upregulated the expression of CD39, Helios, CTLA-4, and CD103 in iTregs, enhancing their immunosuppressive capacity. In a naive CD4+ T cell transfer colitis model, co-transfer of naive CD8+ T cells ameliorated colitis by boosting iTreg-mediated suppression of Th1 and Th17 responses. Mechanistically, we found that CD8+ T cells regulate iTreg phenotypes through a ROS/TGF-beta signaling axis, with IRF4 in CD8+ T cells playing a central role. Furthermore, CD8+ T cell-primed iTregs exhibited superior therapeutic efficacy in an autoimmune arthritis model by suppressing Th1/Th17 responses and preserving endogenous Treg populations. These findings reveal a novel role for CD8+ T cells in supporting iTreg-mediated immune regulation and suggest a promising approach for enhancing Treg-based therapies in autoimmune diseases.