title: Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants.
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.
authors.affiliation: Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, Napoli, Italy.|Unità di NeuroImmunologia, Fondazione Santa Lucia, Roma, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: De Rosa
authors.affiliation: Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, Napoli, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Galgani
authors.affiliation: Dipartimento di Biologia, Complesso Universitario di Monte Sant'Angelo, Università di Napoli ''Federico II'', Napoli, Italy.
authors.forename: Antonio
authors.identifier: http://orcid.org/0000-0001-6882-9518
authors.initials: A
authors.lastname: Porcellini
authors.affiliation: Unità di NeuroImmunologia, Fondazione Santa Lucia, Roma, Italy.|Dipartimento di Medicina e Chirurgia, Università di Salerno, Baronissi Campus, Baronissi, Salerno, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Colamatteo
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli ''Federico II'', Napoli, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Santopaolo
authors.affiliation: Dipartimento di Biologia, Complesso Universitario di Monte Sant'Angelo, Università di Napoli ''Federico II'', Napoli, Italy.
authors.forename: Candida
authors.initials: C
authors.lastname: Zuchegna
authors.affiliation: Dipartimento di Biologia, Complesso Universitario di Monte Sant'Angelo, Università di Napoli ''Federico II'', Napoli, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Romano
authors.affiliation: Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, Napoli, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: De Simone
authors.affiliation: Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, Napoli, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Procaccini
authors.affiliation: Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, Napoli, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: La Rocca
authors.affiliation: Dipartimento di Neuroscienze e Scienze Riproduttive ed Odontostomatologiche, Università di Napoli ''Federico II'', Napoli, Italy.
authors.forename: Pietro Biagio
authors.initials: PB
authors.lastname: Carrieri
authors.affiliation: Dipartimento di Neurologia, Centro Regionale Sclerosi Multipla, Azienda Ospedaliera "A. Cardarelli", Napoli, Italy.
authors.forename: Giorgia Teresa
authors.initials: GT
authors.lastname: Maniscalco
authors.affiliation: Centro Neurologico Terapie Sperimentali, Dipartimento di Neuroscienze, Salute Mentale e Organi di Senso, "Sapienza" Università di Roma, Roma, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Salvetti
authors.affiliation: Centro Neurologico Terapie Sperimentali, Dipartimento di Neuroscienze, Salute Mentale e Organi di Senso, "Sapienza" Università di Roma, Roma, Italy.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Buscarinu
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Università di Napoli ''Federico II'', Napoli, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Franzese
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Università di Napoli ''Federico II'', Napoli, Italy.
authors.forename: Enza
authors.initials: E
authors.lastname: Mozzillo
authors.affiliation: Department of Medicine, David Geffen School of Medicine, University California of Los Angeles, Los Angeles, California, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: La Cava
authors.affiliation: Dipartimento di Medicina e Chirurgia, Università di Salerno, Baronissi Campus, Baronissi, Salerno, Italy.|Istituto di Ricovero e Cura a Carattere Scientifico MultiMedica, Milano, Italy.
authors.forename: Giuseppe
authors.identifier: http://orcid.org/0000-0001-9429-0616
authors.initials: G
authors.lastname: Matarese
mesh_terms: D000328:Adult; D017398:Alternative Splicing; D015551:Autoimmunity; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000145:classification / Q000276:immunology / Q000378:metabolism; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005091:Exons; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D055785:Gene Knockdown Techniques; D014644:Genetic Variation; D006019:Glycolysis / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D055442:Metabolome; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010084:Oxidation-Reduction; D010751:Phosphopyruvate Hydratase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000145:classification / Q000276:immunology* / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C418974:FOXP3 protein, human; D005227:Fatty Acids; D051858:Forkhead Transcription Factors; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D025521:Tumor Suppressor Proteins; C095157:ENO1 protein, human; D010751:Phosphopyruvate Hydratase