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. 2021 Jul 13;54(7):1543-1560.e6.
doi: 10.1016/j.immuni.2021.04.014. Epub 2021 May 17.

Signals of pseudo-starvation unveil the amino acid transporter SLC7A11 as key determinant in the control of Treg cell proliferative potential

Claudio Procaccini  1 , Silvia Garavelli  2 , Fortunata Carbone  1 , Dario Di Silvestre  3 , Claudia La Rocca  2 , Dario Greco  4 , Alessandra Colamatteo  5 , Maria Teresa Lepore  2 , Claudia Russo  6 , Giusy De Rosa  5 , Deriggio Faicchia  2 , Francesco Prattichizzo  7 , Sarah Grossi  8 , Paola Campomenosi  8 , Fabio Buttari  9 , Pierluigi Mauri  3 , Antonio Uccelli  10 , Marco Salvetti  11 , Vincenzo Brescia Morra  12 , Danila Vella  13 , Mario Galgani  14 , Maria Mottola  15 , Bruno Zuccarelli  15 , Roberta Lanzillo  12 , Giorgia Teresa Maniscalco  16 , Diego Centonze  17 , Paola de Candia  18 , Giuseppe Matarese  19
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Free article

Signals of pseudo-starvation unveil the amino acid transporter SLC7A11 as key determinant in the control of Treg cell proliferative potential

Claudio Procaccini et al. Immunity. .
Free article

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: SLC7A11; Treg cells; autoimmunity; dimethyl fumarate; leptin; metabolism; multiple sclerosis; proliferation; starvation; xCT.

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Conflict of interest statement

Declaration of interests 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.

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