T Helper Cell Activation and Expansion Is Sensitive to Glutaminase Inhibition under Both Hypoxic and Normoxic Conditions

Immune responses often take place where nutrients and O2 availability are limited. This has an impact on T cell metabolism and influences activation and effector functions. T cell proliferation and expansion are associated with increased consumption of glutamine which is needed in a number of metabo...

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Published in:	PloS one Vol. 11; no. 7; p. e0160291
Main Authors:	Sener, Zeynep, Cederkvist, Fritjof H, Volchenkov, Roman, Holen, Halvor L, Skålhegg, Bjørn S
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 28-07-2016 Public Library of Science (PLoS)
Subjects:	Ammonia Antigens, CD - metabolism Availability Biology and Life Sciences Biosynthesis Cancer CCR6 protein CD25 antigen CD28 antigen CD3 antigen CD4 antigen Cell activation Cell growth Cell Proliferation Cells, Cultured CXCR3 protein Cytokines Cytokines - secretion Cytoplasm Dehydrogenases Deprivation Enzymes Expansion Glutamate-ammonia ligase Glutaminase Glutaminase - antagonists & inhibitors Glutamine Glutamine - administration & dosage Helper cells Humans Hypoxia Immune response Immunology Inhibition Isoforms Kidneys Kinases Localization Lymphocyte Activation Lymphocytes Lymphocytes T Medicine and Health Sciences Metabolic pathways Metabolism Mitochondria Mitochondria - enzymology Nutrients Nutrition Oxygen - metabolism Physical Sciences Physiological aspects Receptors Receptors, Chemokine - metabolism T cell receptors T cells T-Lymphocytes, Helper-Inducer - cytology T-Lymphocytes, Helper-Inducer - enzymology T-Lymphocytes, Helper-Inducer - metabolism United States
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Summary:	Immune responses often take place where nutrients and O2 availability are limited. This has an impact on T cell metabolism and influences activation and effector functions. T cell proliferation and expansion are associated with increased consumption of glutamine which is needed in a number of metabolic pathways and regulate various physiological processes. The first step in endogenous glutamine metabolism is reversible and is regulated by glutaminase (GLS1 and GLS2) and glutamine synthase (GLUL). There are two isoforms of GLS1, Kidney type glutaminase (KGA) and Glutaminase C (GAC). The aim of this study is to investigate the expression, localization and role of GLS1 and GLUL in naïve and activated human CD4+ T cells stimulated through the CD3 and CD28 receptors under normoxia and hypoxia. In proliferating cells, GAC was upregulated and KGA was downregulated, and both enzymes were located to the mitochondria irrespective of O2 levels. By contrast GLUL is localized to the cytoplasm and was upregulated under hypoxia. Proliferation was dependent on glutamine consumption, as glutamine deprivation and GLS1 inhibition decreased proliferation and expression of CD25 and CD226, regardless of O2 availability. Again irrespective of O2, GLS1 inhibition decreased the proportion of CCR6 and CXCR3 expressing CD4+ T cells as well as cytokine production. We propose that systemic Th cell activation and expansion might be dependent on glutamine but not O2 availability.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Competing Interests: The authors have no conflicting financial interests. Dr. Halvor L. Holen is currently employed by Rheumatech AS and Dr. Roman Volchenkov is partly employed by Rheumatech AS. This does not alter the authors’ adherence to all of the PLOS ONE policies on sharing data and materials. Conceptualization: ZS FHC RV HLH BSS. Formal analysis: ZS. Funding acquisition: BSS. Methodology: ZS FHC. Project administration: BSS. Supervision: BSS HLH. Validation: ZS FHC. Visualization: ZS. Writing - original draft: ZS. Writing - review & editing: FHC RV HLH BSS.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0160291