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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Alternative Splicing
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Autoimmunity
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Biomarkers, Tumor / antagonists & inhibitors
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism
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CD4-Positive T-Lymphocytes / classification
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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Case-Control Studies
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Exons
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Fatty Acids / metabolism
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Female
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Forkhead Transcription Factors / antagonists & inhibitors
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Forkhead Transcription Factors / genetics*
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Forkhead Transcription Factors / metabolism
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Gene Knockdown Techniques
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Genetic Variation
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Glycolysis / genetics*
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Humans
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In Vitro Techniques
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Male
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Metabolome
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Middle Aged
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Multiple Sclerosis, Relapsing-Remitting / genetics
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Multiple Sclerosis, Relapsing-Remitting / immunology
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Multiple Sclerosis, Relapsing-Remitting / metabolism
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Oxidation-Reduction
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Phosphopyruvate Hydratase / antagonists & inhibitors
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Phosphopyruvate Hydratase / genetics
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Phosphopyruvate Hydratase / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, Antigen, T-Cell / metabolism
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Signal Transduction / immunology
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T-Lymphocytes, Regulatory / classification
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / metabolism*
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Tumor Suppressor Proteins / antagonists & inhibitors
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
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Young Adult
Substances
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Biomarkers, Tumor
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DNA-Binding Proteins
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FOXP3 protein, human
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Fatty Acids
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Forkhead Transcription Factors
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RNA, Messenger
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Receptors, Antigen, T-Cell
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Tumor Suppressor Proteins
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ENO1 protein, human
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Phosphopyruvate Hydratase