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Anaplerotic Metabolism of Alloreactive T Cells Provides a Metabolic Approach To Treat Graft-Versus-Host Disease
- Source :
- Journal of Pharmacology and Experimental Therapeutics. 351:298-307
- Publication Year :
- 2014
- Publisher :
- American Society for Pharmacology & Experimental Therapeutics (ASPET), 2014.
-
Abstract
- T-cell activation requires increased ATP and biosynthesis to support proliferation and effector function. Most models of T-cell activation are based on in vitro culture systems and posit that aerobic glycolysis is employed to meet increased energetic and biosynthetic demands. By contrast, T cells activated in vivo by alloantigens in graft-versus-host disease (GVHD) increase mitochondrial oxygen consumption, fatty acid uptake, and oxidation, with small increases of glucose uptake and aerobic glycolysis. Here we show that these differences are not a consequence of alloactivation, because T cells activated in vitro either in a mixed lymphocyte reaction to the same alloantigens used in vivo or with agonistic anti-CD3/anti-CD28 antibodies increased aerobic glycolysis. Using targeted metabolic (13)C tracer fate associations, we elucidated the metabolic pathway(s) employed by alloreactive T cells in vivo that support this phenotype. We find that glutamine (Gln)-dependent tricarboxylic acid cycle anaplerosis is increased in alloreactive T cells and that Gln carbon contributes to ribose biosynthesis. Pharmacological modulation of oxidative phosphorylation rapidly reduces anaplerosis in alloreactive T cells and improves GVHD. On the basis of these data, we propose a model of T-cell metabolism that is relevant to activated lymphocytes in vivo, with implications for the discovery of new drugs for immune disorders.
- Subjects :
- Isoantigens
CD3 Complex
Glutamine
Ribose
T-Lymphocytes
Citric Acid Cycle
Graft vs Host Disease
Oxidative phosphorylation
Biology
Lymphocyte Activation
Oxidative Phosphorylation
Mice
Immune system
CD28 Antigens
In vivo
Animals
Glycolysis
Pharmacology
Metabolism
Inflammation, Immunopharmacology, and Asthma
Citric acid cycle
Metabolic pathway
Biochemistry
Anaerobic glycolysis
Molecular Medicine
Female
Subjects
Details
- ISSN :
- 15210103 and 00223565
- Volume :
- 351
- Database :
- OpenAIRE
- Journal :
- Journal of Pharmacology and Experimental Therapeutics
- Accession number :
- edsair.doi.dedup.....e62ee2574e104f8c8a74db6b80856842