MicroRNA-142-3p shuttling in extracellular vesicles marks regulatory T cell dysfunction in multiple sclerosis

CD4⁺CD25^hiFoxP3⁺ regulatory T cells (T_reg cells) are key controllers of immune self-tolerance, and their suppressive function is impaired in people with relapsing-remitting multiple sclerosis (pwRR-MS). Because the mechanisms underlying this condition are still ill-defined, we investigated the role of T_reg cell-derived extracellular vesicles (T_reg-EVs) in T_reg cell dysfunction observed in pwRR-MS. We found that T_reg-EVs from healthy individuals inhibit CD4⁺ conventional T (T_conv) cells by shuttling miR-142-3p from the T_reg cell to the T_conv cell. There, miR-142-3p down-regulated mRNAs necessary for T_conv cell growth and effector functions, such as the redox controller cystine carrier SLC7A11. However, T_reg cells from pwRR-MS released EVs containing reduced amounts of miR-142-3p, resulting in impaired suppressive function. Furthermore, T_reg-EV miR-142-3p inversely correlated with the disability score and gadolinium-enhancing lesions in pwRR-MS. Together, our results elucidate a molecular mechanism involving miR-142-3p shuttled by T_reg-EVs in the control of immune self-tolerance and unveil its pathogenetic implications in human autoimmunity.