Abstract
Full T cell activation requires TCR engagement (signal 1) in the context of costimulation (signal 2). Costimulation is required for maximal expression of effector cytokines and prevention of T cell anergy. It has become increasingly clear that another major function of costimulation is to up-regulate the metabolic machinery necessary for T cell function. In this report we demonstrate that anergic T cells are metabolically anergic, in that upon full stimulation (signals 1 plus 2) they fail to up-regulate the machinery necessary to support increased metabolism. These findings suggest that one mechanism responsible for the maintenance of T cell anergy is failure to up-regulate the metabolic machinery. Furthermore, we demonstrate that by blocking leucine, glucose, and energy metabolism, T cell activation is mitigated. Additionally, inhibition of these metabolic pathways during T cell activation leads to anergy in Th1-differentiated cells. Overall, our findings extend the role of T cell metabolism in regulating T cell function.
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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AMP-Activated Protein Kinases / drug effects
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AMP-Activated Protein Kinases / immunology*
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AMP-Activated Protein Kinases / metabolism
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Aminoimidazole Carboxamide / analogs & derivatives
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Aminoimidazole Carboxamide / pharmacology
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Animals
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Antibodies, Monoclonal / pharmacology
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CD28 Antigens / immunology
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CD3 Complex / immunology
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Cell Line
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Clonal Anergy*
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Cytochromes c / immunology
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Energy Metabolism / drug effects*
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Energy Metabolism / immunology
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Glucose / immunology
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Glucose / metabolism
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Hypoglycemic Agents / pharmacology
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Immunologic Factors / pharmacology
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Leucine / analogs & derivatives
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Leucine / immunology
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Leucine / metabolism
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Lymphocyte Activation / drug effects
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Lymphocyte Activation / immunology*
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Metabolic Networks and Pathways / drug effects
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Metabolic Networks and Pathways / immunology
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Mice
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Receptors, Antigen, T-Cell / immunology*
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Receptors, Antigen, T-Cell / metabolism
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Ribonucleotides / pharmacology
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T-Lymphocytes / drug effects
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism
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Up-Regulation / drug effects
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Up-Regulation / immunology
Substances
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Antibodies, Monoclonal
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CD28 Antigens
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CD3 Complex
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Hypoglycemic Agents
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Immunologic Factors
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Receptors, Antigen, T-Cell
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Ribonucleotides
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Aminoimidazole Carboxamide
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Cytochromes c
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AMP-Activated Protein Kinases
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AICA ribonucleotide
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Leucine
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Glucose