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: Veronica De Rosa, Mario Galgani, Antonio Porcellini, Alessandra Colamatteo, Marianna Santopaolo, Candida Zuchegna, Antonella Romano, Salvatore De Simone, Claudio Procaccini, Claudia La Rocca, Pietro Biagio Carrieri, Giorgia Teresa Maniscalco, Marco Salvetti, Maria Chiara Buscarinu, Adriana Franzese, Enza Mozzillo, Antonio La Cava, Giuseppe Matarese
• Journal: Nature immunology (Nat Immunol) Vol. 16 Issue 11 Pg. 1174-84 (Nov 2015) ISSN: 1529-2916 [Electronic] United States
• PMID: 26414764 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• DNA-Binding Proteins
• FOXP3 protein, human
• Fatty Acids
• Forkhead Transcription Factors
• RNA, Messenger
• Receptors, Antigen, T-Cell
• Tumor Suppressor Proteins
• ENO1 protein, human
• Phosphopyruvate Hydratase

Topics

• Adult
• Alternative Splicing
• Autoimmunity
• Biomarkers, Tumor (antagonists & inhibitors, genetics, metabolism)
• CD4-Positive T-Lymphocytes (classification, immunology, metabolism)
• Case-Control Studies
• DNA-Binding Proteins (antagonists & inhibitors, genetics, metabolism)
• Exons
• Fatty Acids (metabolism)
• Female
• Forkhead Transcription Factors (antagonists & inhibitors, genetics, metabolism)
• Gene Knockdown Techniques
• Genetic Variation
• Glycolysis (genetics)
• Humans
• In Vitro Techniques
• Male
• Metabolome
• Middle Aged
• Multiple Sclerosis, Relapsing-Remitting (genetics, immunology, metabolism)
• Oxidation-Reduction
• Phosphopyruvate Hydratase (antagonists & inhibitors, genetics, metabolism)
• RNA, Messenger (genetics, metabolism)
• Receptors, Antigen, T-Cell (metabolism)
• Signal Transduction (immunology)
• T-Lymphocytes, Regulatory (classification, immunology, metabolism)
• Tumor Suppressor Proteins (antagonists & inhibitors, genetics, metabolism)
• Young Adult