Foxp3 Reprograms T Cell Metabolism to Function in Low-Glucose, High-Lactate Environments

Immune cells function in diverse metabolic environments. Tissues with low glucose and high lactate concentrations, such as the intestinal tract or ischemic tissues, frequently require immune responses to be more pro-tolerant, avoiding unwanted reactions against self-antigens or commensal bacteria. T...

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Published in:Cell metabolism Vol. 25; no. 6; p. 1282
Main Authors: Angelin, Alessia, Gil-de-Gómez, Luis, Dahiya, Satinder, Jiao, Jing, Guo, Lili, Levine, Matthew H, Wang, Zhonglin, Quinn, 3rd, William J, Kopinski, Piotr K, Wang, Liqing, Akimova, Tatiana, Liu, Yujie, Bhatti, Tricia R, Han, Rongxiang, Laskin, Benjamin L, Baur, Joseph A, Blair, Ian A, Wallace, Douglas C, Hancock, Wayne W, Beier, Ulf H
Format: Journal Article
Language:English
Published: United States 06.06.2017
Subjects:
Animals
Cell Line
Cellular Microenvironment - genetics
Cellular Microenvironment - immunology
Cellular Reprogramming - genetics
Cellular Reprogramming - immunology
Forkhead Transcription Factors - genetics
Forkhead Transcription Factors - immunology
Glucose - genetics
Glucose - immunology
Glycolysis - genetics
Glycolysis - immunology
Humans
Lactic Acid - immunology
Mice
Mice, Inbred BALB C
Mice, Knockout
Oxidative Phosphorylation
Proto-Oncogene Proteins c-myc - genetics
Proto-Oncogene Proteins c-myc - immunology
T-Lymphocytes, Regulatory - immunology
immunometabolism
T cell metabolism
immune regulation
ISSN:1932-7420, 1932-7420
Online Access:Get more information
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Summary:Immune cells function in diverse metabolic environments. Tissues with low glucose and high lactate concentrations, such as the intestinal tract or ischemic tissues, frequently require immune responses to be more pro-tolerant, avoiding unwanted reactions against self-antigens or commensal bacteria. T-regulatory cells (Tregs) maintain peripheral tolerance, but how Tregs function in low-glucose, lactate-rich environments is unknown. We report that the Treg transcription factor Foxp3 reprograms T cell metabolism by suppressing Myc and glycolysis, enhancing oxidative phosphorylation, and increasing nicotinamide adenine dinucleotide oxidation. These adaptations allow Tregs a metabolic advantage in low-glucose, lactate-rich environments; they resist lactate-mediated suppression of T cell function and proliferation. This metabolic phenotype may explain how Tregs promote peripheral immune tolerance during tissue injury but also how cancer cells evade immune destruction in the tumor microenvironment. Understanding Treg metabolism may therefore lead to novel approaches for selective immune modulation in cancer and autoimmune diseases.
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ISSN:1932-7420
1932-7420
DOI:10.1016/j.cmet.2016.12.018