MicroRNA-142-3p shuttling in extracellular vesicles marks regulatory T cell dysfunction in multiple sclerosis
CD4<sup>+</sup>CD25<sup>hi</sup>FoxP3<sup>+</sup> regulatory T cells (T<sub>reg</sub> 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<sub>reg</sub> cell-derived extracellular vesicles (T<sub>reg</sub>-EVs) in T<sub>reg</sub> cell dysfunction observed in pwRR-MS. We found that T<sub>reg</sub>-EVs from healthy individuals inhibit CD4<sup>+</sup> conventional T (T<sub>conv</sub>) cells by shuttling miR-142-3p from the T<sub>reg</sub> cell to the T<sub>conv</sub> cell. There, miR-142-3p down-regulated mRNAs necessary for T<sub>conv</sub> cell growth and effector functions, such as the redox controller cystine carrier <i>SLC7A11</i>. However, T<sub>reg</sub> cells from pwRR-MS released EVs containing reduced amounts of miR-142-3p, resulting in impaired suppressive function. Furthermore, T<sub>reg</sub>-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<sub>reg</sub>-EVs in the control of immune self-tolerance and unveil its pathogenetic implications in human autoimmunity.
Authors
- Paolo Bergese (ORCID: https://orcid.org/0000-0002-4652-2168)
- Gianmarco Abbadessa (ORCID: https://orcid.org/0000-0001-8912-3055)
- Diego Centonze (ORCID: https://orcid.org/0000-0002-8390-8545)
- Vincenza Dolo (ORCID: https://orcid.org/0000-0003-0424-6676)
- Valentina Bollati (ORCID: https://orcid.org/0000-0002-0370-9598)
- Paola Campomenosi (ORCID: https://orcid.org/0000-0002-8853-1134)
- Francesco Prattichizzo (ORCID: https://orcid.org/0000-0002-2959-2658)
- Claudio Procaccini (ORCID: https://orcid.org/0000-0002-2184-0442)
- Francesca Beretta (ORCID: https://orcid.org/0000-0003-0887-1495)
- Paola D’Antona
- Alessandra Colamatteo (ORCID: https://orcid.org/0000-0002-9693-3985)
- Donatella Carpi (ORCID: https://orcid.org/0000-0002-2645-0582)
- Elisabetta Signoriello (ORCID: https://orcid.org/0000-0001-5753-6752)
- Francesca Brambilla (ORCID: https://orcid.org/0000-0001-9982-6133)
- Fortunata Carbone (ORCID: https://orcid.org/0000-0003-4299-6515)
- Dario Di Silvestre (ORCID: https://orcid.org/0000-0002-7143-6229)
- Annalisa Radeghieri (ORCID: https://orcid.org/0000-0003-2737-1090)
- Alessandra Mandelli (ORCID: https://orcid.org/0000-0002-6494-7776)
- S. Garavelli (ORCID: https://orcid.org/0000-0001-6105-1467)
- Edoardo Dalmato Schilke (ORCID: https://orcid.org/0009-0008-6546-5745)
- Clorinda Fusco (ORCID: https://orcid.org/0009-0008-2158-4304)
- Giusy De Rosa (ORCID: https://orcid.org/0000-0001-7774-9034)
- Antonio Uccelli (ORCID: https://orcid.org/0000-0002-2008-6038)
- Ilaria Giusti (ORCID: https://orcid.org/0000-0002-7982-471X)
- Giuseppe Mele (ORCID: https://orcid.org/0000-0003-4813-8618)
- Claudia La Rocca (ORCID: https://orcid.org/0000-0002-2003-887X)
- Roberta Lanzillo (ORCID: https://orcid.org/0000-0001-6388-8180)
- Marco Salvetti (ORCID: https://orcid.org/0000-0002-0501-8803)
- Ivana Morabito
- Roberto Furlan (ORCID: https://orcid.org/0000-0001-7376-9425)
- Elena Tagliabue (ORCID: https://orcid.org/0000-0002-8153-2599)
- Paola de Candia (ORCID: https://orcid.org/0000-0003-4767-446X)
- Mirjam Hoxha (ORCID: https://orcid.org/0000-0003-1251-2647)
- Simona Bonavita (ORCID: https://orcid.org/0000-0002-8561-9720)
- Ettore Dolcetti (ORCID: https://orcid.org/0000-0002-4594-4895)
- Valentina Mangolini (ORCID: https://orcid.org/0000-0002-5548-7405)
- Fabiana Passaro (ORCID: https://orcid.org/0000-0003-0150-5302)
- Guido Cavaletti (ORCID: https://orcid.org/0000-0003-4128-2406)
- Claudia Russo (ORCID: https://orcid.org/0000-0001-5869-4445)
- Annamaria Finardi (ORCID: https://orcid.org/0000-0002-7909-2600)
- Bruno Zuccarelli
- Giuseppe Matarese (ORCID: https://orcid.org/0000-0001-9429-0616)
- Giacomo Lus (ORCID: https://orcid.org/0000-0002-9457-1124)
- Pierluigi Mauri (ORCID: https://orcid.org/0000-0003-4364-0393)
- Maria Mottola (ORCID: https://orcid.org/0000-0003-3817-7920)
- Fabio Buttari (ORCID: https://orcid.org/0000-0002-6089-4670)
- Ilaria Spatocco
- Vincenzo Brescia Morra (ORCID: https://orcid.org/0000-0003-0462-9618)
Institutions
- University of Insubria (IT)
- University of Rome Tor Vergata (IT)
- Vita-Salute San Raffaele University (IT)
- University of Milan (IT)
- University of L'Aquila (IT)
- Istituto Neurologico Mediterraneo (IT)
- MultiMedica (IT)
- Consorzio Interuniversitario per lo Sviluppo dei Sistemi a Grande Interfase (IT)
- Azienda Ospedaliera San Gerardo (IT)
- Don Carlo Gnocchi Foundation (IT)
- Federico II University Hospital (IT)
- Joint Research Centre (IT)
- University of Campania "Luigi Vanvitelli" (IT)
- Azienda Ospedaliera Universitaria Università degli Studi della Campania Luigi Vanvitelli (IT)
- Institute for Biomedical Research and Innovation (IT)
- IRCCS Ospedale San Raffaele (IT)
- Institute for Experimental Endocrinology and Oncology (IT)
- Ospedale Monaldi (IT)
- Ospedale Policlinico San Martino (IT)
- Fondazione Santa Lucia (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Institute of Biomedical Technologies (IT)
- Imperial College London (GB)
- University of Milano-Bicocca (IT)
- University of Naples Federico II (IT)
- University of Brescia (IT)
- University of Genoa (IT)
- Sapienza University of Rome (IT)
Publication Details
- Journal
- Science Translational Medicine
- Published
- 2025-05-28
- DOI
- https://doi.org/10.1126/scitranslmed.adl1698
- Citations
- 4
- Primary Topic
- Extracellular vesicles in disease
- Type
- article
- Field-Weighted Citation Impact
- 3.22