Itreg cells Ameliorates MOG-induced brain inflammation via endowing DC tolerogenic capacity predominantly via TGF-beta signaling mediated AKT/mTOR pathway inhibition.

BACKGROUND: Certain environmental factors have been known to compromise the suppressive capacity of thymus-derived regulatory T cells (tTregs) while leaving transforming growth factor-beta (TGF-β)-induced Tregs (iTregs) unaffected. The objective of this study is to ascertain whether both Treg subsets exhibit comparable efficacy in regulating brain inflammation through the inhibition of immunogenic dendritic cells (DCs) and instead induce tolerogenic DCs. OBJECTIVES: We aimed to delineate the different therapeutic potential roles of both Treg subsets in promoting the tolerogenic capacity of DCs and elucidate the mechanistic crosstalk between Tregs and DCs. METHODS: The clinical scores of experimental autoimmune encephalomyelitis (EAE) mice were continuously monitored, brain inflammation was assessed through hematoxylin and eosin (H&E) staining, and the presence of brain-infiltrating Th1/Th17 cells as well as splenic CD11c(+) DCs was analyzed using flow cytometry. Additionally, a DC-T coculture assay was conducted, and the underlying mechanisms were determined by western blotting and flow cytometry. RESULTS: iTregs exhibit greater efficacy than tTregs in mitigating brain inflammation in both EAE and EAE provoked by a high-salt diet. iTregs suppress the pro-inflammatory activity of DCs while promoting the generation of a tolerance-inducing DC phenotype. This effect is primarily mediated by membrane-bound TGF-β signaling, rather than through IL-10R signaling, and involves the inhibition of the AKT/mTOR pathway. CONCLUSION: iTreg cells play a pivotal role in orchestrating the formation of a robust immunoregulatory circuit involving tolerogenic DCs, which holds significant promise as a target for the development of innovative immunotherapeutic strategies for autoimmune disorders.