Abstract

Human regulatory T cells (Treg cells) that develop from conventional T cells (Tconv cells) following suboptimal stimulation via the T cell antigen receptor (TCR) (induced Treg cells (iTreg 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 iTreg 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 iTreg 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 Treg cells in health and in autoimmunity.

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Acknowledgements

We thank M.R. Montagna for technical support, and all members of the Laboratory of Immunology at Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche for assistance and support. Supported by the European Union IDEAS Programme European Research Council (“menTORingTregs” 310496 to G.M.), the Fondazione Italiana Sclerosi Multipla (2012/R/11 to G.M.), the Consiglio Nazionale delle Ricerche-Medicina Personalizzata (G.M.), the Ministero della Salute (GR-2010-2315414 to V.D.R.), the Fondo per gli Investimenti della Ricerca di Base (RBFR12I3UB_004 to V.D.R.), the Fondazione Italiana Sclerosi Multipla (2014/R/21 to V.D.R.), the Juvenile Diabetes Research Foundation (1-PNF-2015-115-S-B to M.G.), the US National Institutes of Health (AI109677 to A.L.C.), the PhD Program in Medicina Traslazionale dello Sviluppo e dell'Invecchiamento Attivo, Università degli Studi di Salerno (A.C.), the PhD Program in Medicina Molecolare e Biotecnologie Mediche (M.S.), the PhD Program in Biologia, Università degli Studi di Napoli “Federico II” (A.R.) and the “Fondazione Umberto Veronesi”, Milano (C.Z.).

Author information

Author notes

    • Veronica De Rosa
    • , Mario Galgani
    •  & Antonio Porcellini

    These authors equally contributed to this work.

Affiliations

  1. Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, Napoli, Italy.

    • Veronica De Rosa
    • , Mario Galgani
    • , Salvatore De Simone
    • , Claudio Procaccini
    •  & Claudia La Rocca
  2. Unità di NeuroImmunologia, Fondazione Santa Lucia, Roma, Italy.

    • Veronica De Rosa
    •  & Alessandra Colamatteo
  3. Dipartimento di Biologia, Complesso Universitario di Monte Sant'Angelo, Università di Napoli ''Federico II'', Napoli, Italy.

    • Antonio Porcellini
    • , Candida Zuchegna
    •  & Antonella Romano
  4. Dipartimento di Medicina e Chirurgia, Università di Salerno, Baronissi Campus, Baronissi, Salerno, Italy.

    • Alessandra Colamatteo
    •  & Giuseppe Matarese
  5. Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli ''Federico II'', Napoli, Italy.

    • Marianna Santopaolo
  6. Dipartimento di Neuroscienze e Scienze Riproduttive ed Odontostomatologiche, Università di Napoli ''Federico II'', Napoli, Italy.

    • Pietro Biagio Carrieri
  7. Dipartimento di Neurologia, Centro Regionale Sclerosi Multipla, Azienda Ospedaliera “A. Cardarelli”, Napoli, Italy.

    • Giorgia Teresa Maniscalco
  8. Centro Neurologico Terapie Sperimentali, Dipartimento di Neuroscienze, Salute Mentale e Organi di Senso, “Sapienza” Università di Roma, Roma, Italy.

    • Marco Salvetti
    •  & Maria Chiara Buscarinu
  9. Dipartimento di Scienze Mediche Traslazionali, Università di Napoli ''Federico II'', Napoli, Italy.

    • Adriana Franzese
    •  & Enza Mozzillo
  10. Department of Medicine, David Geffen School of Medicine, University California of Los Angeles, Los Angeles, California, USA.

    • Antonio La Cava
  11. Istituto di Ricovero e Cura a Carattere Scientifico MultiMedica, Milano, Italy.

    • Giuseppe Matarese

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Contributions

V.D.R., M.G., A.P., A.L.C. and G.M. designed the study, interpreted data and wrote the manuscript; V.D.R., M.G., A.P., A.C., M.S., C.Z., A.R., S.D.S., C.P. and C.L.R. performed the experiments; V.D.R., M.G., A.P. and A.L.C. analyzed the data and interpreted results; V.D.R., M.G., A.P. and C.P. performed statistical analyses; and P.B.C., G.T.M., M.S., M.C.B., A.F. and E.M. obtained human samples from patients and were involved in discussions about data.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Giuseppe Matarese.

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DOI

https://doi.org/10.1038/ni.3269

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