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

CD4 + CD25 hi FoxP3 + 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.