@article{8fac19105ee54aa99f9d3ae573000d75,
title = "Signals of pseudo-starvation unveil the amino acid transporter SLC7A11 as key determinant in the control of Treg cell proliferative potential",
abstract = "Human CD4+CD25hiFOXP3+ regulatory T (Treg) cells are key players in the control of immunological self-tolerance and homeostasis. Here, we report that signals of pseudo-starvation reversed human Treg cell in vitro anergy through an integrated transcriptional response, pertaining to proliferation, metabolism, and transmembrane solute carrier transport. At the molecular level, the Treg cell proliferative response was dependent on the induction of the cystine/glutamate antiporter solute carrier (SLC)7A11, whose expression was controlled by the nuclear factor erythroid 2-related factor 2 (NRF2). SLC7A11 induction in Treg cells was impaired in subjects with relapsing-remitting multiple sclerosis (RRMS), an autoimmune disorder associated with reduced Treg cell proliferative capacity. Treatment of RRMS subjects with dimethyl fumarate (DMF) rescued SLC7A11 induction and fully recovered Treg cell expansion. These results suggest a previously unrecognized mechanism that may account for the progressive loss of Treg cells in autoimmunity and unveil SLC7A11 as major target for the rescue of Treg cell proliferation.",
keywords = "autoimmunity, dimethyl fumarate, leptin, metabolism, multiple sclerosis, proliferation, SLC7A11, starvation, Treg cells, xCT",
author = "Claudio Procaccini and Silvia Garavelli and Fortunata Carbone and {Di Silvestre}, Dario and {La Rocca}, Claudia and Dario Greco and Alessandra Colamatteo and Lepore, {Maria Teresa} and Claudia Russo and {De Rosa}, Giusy and Deriggio Faicchia and Francesco Prattichizzo and Sarah Grossi and Paola Campomenosi and Fabio Buttari and Pierluigi Mauri and Antonio Uccelli and Marco Salvetti and {Brescia Morra}, Vincenzo and Danila Vella and Mario Galgani and Maria Mottola and Bruno Zuccarelli and Roberta Lanzillo and Maniscalco, {Giorgia Teresa} and Diego Centonze and {de Candia}, Paola and Giuseppe Matarese",
note = "Funding Information: G.M. reports receiving research grant support from Merck, Biogen, and Novartis and advisory board fees from Merck, Biogen, Novartis, and Roche. M.S. received research grant support and advisory board fees from Biogen, Merck, Novartis, Roche, and Sanofi. A.U. received research grant support from Merck, Biogen, and Novartis and advisory board fees from Merck, Biogen, Novartis, Sanofi-Genzyme, and Roche. D.C. is an advisory board member of Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. His preclinical and clinical research was supported by grants from Bayer Schering, Biogen Idec, Celgene, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. Funding Information: G.M. is funded by Fondazione Italiana Sclerosi Multipla (FISM; grants 2016/R/18 and 2018/S/5), Progetti di Rilevante Interesse Nazionale (PRIN; grant 2017 K55HLC 001), and Ministero della Salute (grant RF-2019-12371111). P.d.C. is supported by the National Multiple Sclerosis Society (NMSS; grant PP-1606-24687), FISM (grants 2016/R/10 and 2018/R/4), and the Juvenile Diabetes Research Foundation (JDRF; grant 1-SRA-2018-477-S-B). C.P. F.B. and F.C. are supported by the Italian Ministry of Health (grants GR-2016-02363749 to C.P. GR-2018-12366154 to C.P. and F.B. GR-2016-02362380 to F.B. and GR-2016-02363725 to F.C.). M.G. is supported by the JDRF (grant 2-SRA-2018-479-S-B) and the NMSS (grant PP-1804-30725). S. Grossi is a PhD student of biotechnology, biosciences, and surgical technology at Universit? degli Studi dell'Insubria. The authors thank Maria Rosaria Montagna and Salvatore De Simone for technical help. This work has also been supported by Italian Ministry of Health Ricerca Corrente - IRCCS MultiMedica. The funders had no role in study design, data analysis, decision to publish, or preparation of the manuscript. Schematic figures were created with images adapted from Smart Servier Medical Art (http://www.servier.fr/servier-medical-art). C.P. S. Garavelli, F.C. C.L.R. A.C. M.T.L. C.R. G.D.R. and D.F. performed and analyzed the experiments; D.G. produced microarray data and first analysis; D.D.S. D.V. and P.d.C. analyzed microarray data; S. Garavelli, S. Grossi, and P.C. contributed to data acquisition and analysis (droplet digital PCR experiments); F.B. A.U. M.S. V.B.M. R.L. G.T.M. and D.C. recruited subjects with RRMS, analyzed clinical data, and were involved in discussions about the data; M.M. and B.Z. provided samples from healthy controls; C.P. and P.d.C. performed statistical analyses; F.P. P.M. and M.G. provided critical advice and were involved in the discussion of the data; C.P. P.d.C. and G.M. wrote the manuscript; P.d.C. and G.M. supervised all the aspects of the experiments and are co-senior authors of this work; and G.M. conceived the study. G.M. reports receiving research grant support from Merck, Biogen, and Novartis and advisory board fees from Merck, Biogen, Novartis, and Roche. M.S. received research grant support and advisory board fees from Biogen, Merck, Novartis, Roche, and Sanofi. A.U. received research grant support from Merck, Biogen, and Novartis and advisory board fees from Merck, Biogen, Novartis, Sanofi-Genzyme, and Roche. D.C. is an advisory board member of Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. His preclinical and clinical research was supported by grants from Bayer Schering, Biogen Idec, Celgene, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. Funding Information: G.M. is funded by Fondazione Italiana Sclerosi Multipla (FISM; grants 2016/R/18 and 2018/S/5 ), Progetti di Rilevante Interesse Nazionale (PRIN; grant 2017 K55HLC 001 ), and Ministero della Salute (grant RF-2019-12371111 ). P.d.C. is supported by the National Multiple Sclerosis Society (NMSS; grant PP-1606-24687 ), FISM (grants 2016/R/10 and 2018/R/4 ), and the Juvenile Diabetes Research Foundation (JDRF; grant 1-SRA-2018-477-S-B ). C.P., F.B., and F.C. are supported by the Italian Ministry of Health (grants GR-2016-02363749 to C.P., GR-2018-12366154 to C.P. and F.B., GR-2016-02362380 to F.B., and GR-2016-02363725 to F.C.). M.G. is supported by the JDRF (grant 2-SRA-2018-479-S-B ) and the NMSS (grant PP-1804-30725 ). S. Grossi is a PhD student of biotechnology, biosciences, and surgical technology at Universit{\`a} degli Studi dell{\textquoteright}Insubria. The authors thank Maria Rosaria Montagna and Salvatore De Simone for technical help. This work has also been supported by Italian Ministry of Health Ricerca Corrente - IRCCS MultiMedica. The funders had no role in study design, data analysis, decision to publish, or preparation of the manuscript. Schematic figures were created with images adapted from Smart Servier Medical Art ( http://www.servier.fr/servier-medical-art ). Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = jul,
doi = "10.1016/j.immuni.2021.04.014",
language = "English",
pages = "1543--1560.e6",
journal = "Immunity",
issn = "1074-7613",
publisher = "Cell Press",
}