Secondary progressive multiple sclerosis (SPMS) is an autoimmune neurodegenerative disease characterized not only by white matter compromission, but also by synaptopathy in the grey matter. This lead to an unbalanced Glutamatergic/GABAergic transmission mediated by T lymphocytes infiltration. Here, we explore the possible synaptoprotective effects of Siponimod, a sphingosine 1-phosphate receptor (S1PR) modulator, demonstrated to reduce the accumulation of disability and grey matter damage in SPMS patients.Chimeric experiments were performed by incubating human T cells on murine (C57BL/6) corticostriatal slices. Electrophysiological recordings were conducted on striatal neurons incubated with T cells from healthy individuals (HC), and non-active SPMS patients, 7 of whom received siponimod treatment. Homologous non-chimeric experiments were executed using T lymphocytes from EAE mice spleens incubated with specific S1PR agonists and antagonists to identify the receptor involved in siponimod-mediated synaptic recovery.All the kinetic parameters of sEPSCs recorded with T lymphocytes from SPMS patients were significantly increased compared to HC. This effect was rescued by the tumor necrosis factor (TNF) antagonist, etanercept, indicating that the increased kinetics were TNF-mediated. Importantly, T cells from siponimod-treated SPMS patients did not induce synaptic toxicity compared to non-siponimod-treated SPMS patients. Experiments with EAE T lymphocytes confirmed that siponimod treatment led to the recovery of sEPSC decay time and half-width compared to vehicle treatment and revealed that this synaptoprotective effect of siponimod was mediated by the modulation of S1P5Rs.