Background: mucosal associated invariant T (MAIT) cells are innate-like T cells expressing an invariant TCR ? chain with a limited number of ?-chains. MAIT cells recognize antigens presented by the major histocompatibility complex-related molecule 1 (MR1) derived from bacterial metabolites of vitamin B2 synthesis. In adult humans, MAIT represent about 10% of CD8+ circulating cells in the blood and they have an effector memory phenotype. Objectives: to characterize MAIT cells phenotype in people with MS (pwMS) Methods: peripheral blood samples were obtained from 10 untreated people diagnosed with Multiple Sclerosis and 9 age and BMI-matched healthy controls (HCs). Cerebrospinal fluid (CSF) samples were obtained from 8 untreated pwMS and 3 HCs. CD8+ MAIT cells were quantified by flow cytometry as CD3+CD8+Va7.2+CD161+ cells. PD-1 expression was determined by mean fluorescent intensity. Cytokine production was determined 24 and 48 hours after in vitro stimulation with anti-CD28 and paraformaldehyde-fixed E. Coli. The production of IFN-?, IL-17A and IL-10 was quantified by intracellular staining. For the proliferation assay MAIT cells and CD4+ and CD8+ T cells were stained with CFSE and co-cultured with E. Coli for 72 hours Results: pwMS showed lower percentages and absolute numbers of CD8+ MAIT cells in the peripheral blood compared to HCs (mean±SD: 8.03±2.99 and 16.97±8.79%, p<0.01; 25±11 and 59±27 cells/uL, p<0.01). CD8+ MAIT cells obtained from pwMS had lower expression of the inhibitory molecule PD-1 on both peripheral blood and CSF samples, compared with HCs and people with other neurological diseases, respectively (mean±SD of PD-1 MFI: 2346.3±1856.1 and 4131±1628, p<0.01). Furthermore, CD8+ MAIT cells obtained from pwMS showed a defective TCR-mediated activation, after in vitro stimulation with E. Coli, resulting in lower levels of IFN-? production (mean±SD: 2.09±1.85 and 14.4±4.06%, p<0.01). Finally, in in vitro experiments we demonstrated that TCR-mediated MAIT cells activation negatively influence CD4+ and CD8+ T cells proliferation. Conclusions: we described lower numbers and a defective activation of MAIT cells in pwMS compared with HCs. The deficits were evident also in CSF samples and not only in peripheral blood samples. Moreover, we described a correlation between MAIT cells activation and CD4 and CD8 T cells proliferation that could link our observations with an autoimmune activation of the adaptive immune system.