Human CD4(+)CD25(hi)FOXP3(+) 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.

Procaccini, C., Garavelli, S., Carbone, F., Di Silvestre, D., La Rocca, C., Greco, D., et al. (2021). Signals of pseudo-starvation unveil the amino acid transporter SLC7A11 as key determinant in the control of Treg cell proliferative potential. IMMUNITY, 54(7), 1543-1560.e6 [10.1016/j.immuni.2021.04.014].

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

Buttari, Fabio;Centonze, Diego;
2021-01-01

Abstract

Human CD4(+)CD25(hi)FOXP3(+) 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.
2021
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/26 - NEUROLOGIA
English
Con Impact Factor ISI
SLC7A11
Treg cells
autoimmunity
dimethyl fumarate
leptin
metabolism
multiple sclerosis
proliferation
starvation
xCT
Adult
Amino Acid Transport System y+
Autoimmunity
Cell Proliferation
Cells, Cultured
Female
Homeostasis
Humans
Immune Tolerance
Male
Multiple Sclerosis, Relapsing-Remitting
NF-E2-Related Factor 2
T-Lymphocytes, Regulatory
https://www.sciencedirect.com/science/article/abs/pii/S107476132100176X?via=ihub
Procaccini, C., Garavelli, S., Carbone, F., Di Silvestre, D., La Rocca, C., Greco, D., et al. (2021). Signals of pseudo-starvation unveil the amino acid transporter SLC7A11 as key determinant in the control of Treg cell proliferative potential. IMMUNITY, 54(7), 1543-1560.e6 [10.1016/j.immuni.2021.04.014].
Procaccini, C; Garavelli, S; Carbone, F; Di Silvestre, D; La Rocca, C; Greco, D; Colamatteo, A; Lepore, Mt; Russo, C; De Rosa, G; Faicchia, D; Prattic...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/282281
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