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Nat Immunol. 2015 Nov;16(11):1174-84. doi: 10.1038/ni.3269. Epub 2015 Sep 28.

Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants.

Author information

1
Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, Napoli, Italy.
2
Unità di NeuroImmunologia, Fondazione Santa Lucia, Roma, Italy.
3
Dipartimento di Biologia, Complesso Universitario di Monte Sant'Angelo, Università di Napoli ''Federico II'', Napoli, Italy.
4
Dipartimento di Medicina e Chirurgia, Università di Salerno, Baronissi Campus, Baronissi, Salerno, Italy.
5
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli ''Federico II'', Napoli, Italy.
6
Dipartimento di Neuroscienze e Scienze Riproduttive ed Odontostomatologiche, Università di Napoli ''Federico II'', Napoli, Italy.
7
Dipartimento di Neurologia, Centro Regionale Sclerosi Multipla, Azienda Ospedaliera "A. Cardarelli", Napoli, Italy.
8
Centro Neurologico Terapie Sperimentali, Dipartimento di Neuroscienze, Salute Mentale e Organi di Senso, "Sapienza" Università di Roma, Roma, Italy.
9
Dipartimento di Scienze Mediche Traslazionali, Università di Napoli ''Federico II'', Napoli, Italy.
10
Department of Medicine, David Geffen School of Medicine, University California of Los Angeles, Los Angeles, California, USA.
11
Istituto di Ricovero e Cura a Carattere Scientifico MultiMedica, Milano, Italy.

Abstract

Human regulatory T cells (T(reg) cells) that develop from conventional T cells (T(conv) cells) following suboptimal stimulation via the T cell antigen receptor (TCR) (induced T(reg) cells (iT(reg) cells)) express the transcription factor Foxp3, are suppressive, and display an active proliferative and metabolic state. Here we found that the induction and suppressive function of iT(reg) cells tightly depended on glycolysis, which controlled Foxp3 splicing variants containing exon 2 (Foxp3-E2) through the glycolytic enzyme enolase-1. The Foxp3-E2-related suppressive activity of iT(reg) cells was altered in human autoimmune diseases, including multiple sclerosis and type 1 diabetes, and was associated with impaired glycolysis and signaling via interleukin 2. This link between glycolysis and Foxp3-E2 variants via enolase-1 shows a previously unknown mechanism for controlling the induction and function of T(reg) cells in health and in autoimmunity.

PMID:
26414764
PMCID:
PMC4868085
DOI:
10.1038/ni.3269
[Indexed for MEDLINE]
Free PMC Article

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