Physical exercise modulates T cell activity and mitigates synaptic dysfunction in multiple sclerosis through vagus nerve engagement.

Physical exercise (PE) exerts beneficial effects in people with multiple sclerosis (pwMS). Preclinical studies in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS, indicate that PE may attenuate key pathological features of the disease, including immune dysregulation and inflammation-driven synaptotoxicity, although the underlying mechanisms remain unclear. Clinical evidence, however, is still limited and fragmented, leaving the disease-modifying potential of PE in MS largely unresolved. Here, we investigated the impact of PE on T cell immunometabolic function and its downstream consequences on synaptotoxicity in both EAE mice and progressive MS (PMS) subjects, also assessing the contribution of vagal innervation to PE-mediated effects in the EAE model. Specifically, we found that PE improved EAE clinical course, by mitigating neuronal damage and modulating peripheral T cell proliferation, activation, and metabolic activity. These beneficial effects were partially blunted by preventive cervical vagotomy, suggesting a role for vagal integrity in mediating PE-driven neuroimmune modulation. In PMS subjects, a structured PE program improved clinical functional outcomes and enhanced mitochondrial respiration in peripheral T cells. Moreover, patch-clamp recordings revealed that glutamatergic synaptotoxicity induced by PMS-derived T cells was abolished following PE. Together, these findings highlight the therapeutic potential and disease-modifying value of PE in MS and suggest the vagal pathway as a key modulator of exercise-induced neuroimmune benefits.