The lactate-FoxO1 axis drives senescence of CD4+ PD-1+ T cells and rheumatoid arthritis progression

Abstract Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease characterized by persistent synovitis, joint destruction, metabolic reprogramming, and premature immune senescence. Despite the established link between serum lactate and disease activity, the specific mechanisms by which this metabolite drives T cell senescence remain poorly understood. Using a collagen-induced arthritis (CIA) model and in vitro CD4 + T cell cultures, we elucidate the mechanistic role of lactate in CD4 + T cell senescence. We found that lactate significantly exacerbated arthritis severity and bone erosion. Lactate directly induced T cell senescence, characterized by increased senescence-associated β-galactosidase activity, elevated γH2AX levels, upregulated P21/P53 expression, and a senescence-associated secretory phenotype (SASP). Importantly, lactate expanded the pathogenic senescent CD4 + PD-1 + subset by upregulating FoxO1, potentially through suppression of AKT phosphorylation. Knockdown or pharmacological inhibition of FoxO1 effectively abolished the lactate-induced PD-1 expression and senescence. Furthermore, targeting lactate transport with the MCT inhibitor CHC significantly ameliorated disease progression and senescence in CIA, showing greater efficacy than inhibiting endogenous lactate production. These findings uncover a novel lactate-FoxO1-PD-1 axis driving RA progression and offer a new strategy to treat RA by targeting T cell senescence.