The Pathogenic Role of T Cell Metabolism and its Effect on Immune Senescence in Autoimmune Diseases and Infection.

Abstract

T cell metabolism constitutes a pivotal regulator of cellular states and disease progression. At the cellular level, the metabolic status of T cells directly governs their function and fate determination. Senescent T cells, for instance, exhibit fundamentally distinct metabolic signatures compared to effector T subsets, underscoring metabolic reprogramming as a critical mechanistic driver of T cell senescence. In pathological contexts, aberrant metabolic rewiring in T cells disrupts differentiation, function, and cellular survival, thereby contributing to disease onset and progression. Notably, the pathological accumulation of senescent T cells observed across chronic inflammatory and autoimmune diseases positions metabolism-driven T cell senescence as a key nexus linking metabolic dysregulation to clinical manifestations. Consequently, targeted modulation of T cell metabolism offers a dual therapeutic potential: direct intervention in cellular states (e.g., delaying senescent phenotypes) and synergistic amelioration of disease pathology through functional immune restoration. This Review summarizes the fundamental principles of T cell metabolic reprogramming, its causative role in propelling T cell senescence, and the dynamic interplay between metabolic dysfunction, T cell senescence, and disease pathogenesis. We specifically dissect these relationships in two immunologically divergent conditions-systemic lupus erythematosus (SLE, exemplifying hyperactive autoimmunity) and chronic infection (Chronic HIV infection, reflecting immune exhaustion)-to establish a mechanistic framework for developing metabolism-targeted immunotherapeutics that precisely restore T cell efficacy.