CD4+CD25hiFoxP3+ regulatory T cells (Treg 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 Treg cell–derived extracellular vesicles (Treg-EVs) in Treg cell dysfunction observed in pwRR-MS. We found that Treg-EVs from healthy individuals inhibit CD4+ conventional T (Tconv) cells by shuttling miR-142-3p from the Treg cell to the Tconv cell. There, miR-142-3p down-regulated mRNAs necessary for Tconv cell growth and effector functions, such as the redox controller cystine carrier SLC7A11. However, Treg cells from pwRR-MS released EVs containing reduced amounts of miR-142-3p, resulting in impaired suppressive function. Furthermore, Treg-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 Treg-EVs in the control of immune self-tolerance and unveil its pathogenetic implications in human autoimmunity.
MicroRNA-142-3p shuttling in extracellular vesicles marks regulatory T cell dysfunction in multiple sclerosis / De Rosa, G.; Russo, C.; Garavelli, S.; Di Silvestre, D.; Spatocco, I.; Mele, G.; Rocca, C. L.; Colamatteo, A.; Carbone, F.; Fusco, C.; Passaro, F.; Carpi, D.; Tagliabue, E.; Prattichizzo, F.; Brambilla, F.; Mauri, P.; Hoxha, M.; Bollati, V.; Giusti, I.; Dolo, V.; D'Antona, P.; Campomenosi, P.; Mangolini, V.; Radeghieri, A.; Bergese, P.; Morabito, I.; Mandelli, A.; Finardi, A.; Beretta, F.; Schilke, E. D.; Cavaletti, G.; Dolcetti, E.; Buttari, F.; Abbadessa, G.; Bonavita, S.; Lus, G.; Signoriello, E.; Lanzillo, R.; Morra, V. B.; Mottola, M.; Zuccarelli, B.; Uccelli, A.; Salvetti, M.; Centonze, D.; Furlan, R.; Matarese, G.; Procaccini, C.; De Candia, P.. - In: SCIENCE TRANSLATIONAL MEDICINE. - ISSN 1946-6234. - 17:800(2025). [10.1126/scitranslmed.adl1698]
MicroRNA-142-3p shuttling in extracellular vesicles marks regulatory T cell dysfunction in multiple sclerosis
Russo C.;Brambilla F.;Beretta F.;Mottola M.;Furlan R.;
2025-01-01
Abstract
CD4+CD25hiFoxP3+ regulatory T cells (Treg 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 Treg cell–derived extracellular vesicles (Treg-EVs) in Treg cell dysfunction observed in pwRR-MS. We found that Treg-EVs from healthy individuals inhibit CD4+ conventional T (Tconv) cells by shuttling miR-142-3p from the Treg cell to the Tconv cell. There, miR-142-3p down-regulated mRNAs necessary for Tconv cell growth and effector functions, such as the redox controller cystine carrier SLC7A11. However, Treg cells from pwRR-MS released EVs containing reduced amounts of miR-142-3p, resulting in impaired suppressive function. Furthermore, Treg-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 Treg-EVs in the control of immune self-tolerance and unveil its pathogenetic implications in human autoimmunity.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
