Abstract
Energy metabolism is essential for T cell function. However, how persistent antigenic stimulation affects T cell metabolism is unknown. Here, we report that long-term in vivo antigenic exposure induced a specific deficit in numerous metabolic enzymes. Accordingly, T cells exhibited low basal glycolytic flux and limited respiratory capacity. Strikingly, blockade of inhibitory receptor PD-1 stimulated the production of IFNγ in chronic T cells, but failed to shift their metabolism towards aerobic glycolysis, as observed in effector T cells. Instead, chronic T cells appeared to rely on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) to produce ATP for IFNγ synthesis. Check-point blockade, however, increased mitochondrial production of superoxide and reduced viability and effector function. Thus, in the absence of a glycolytic switch, PD-1-mediated inhibition appears essential for limiting oxidative metabolism linked to effector function in chronic T cells, thereby promoting survival and functional fitness.
Keywords:
PD-1; T lymphocytes; immunology; inflammation; metabolism; mouse.
© 2018, Bettonville et al.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / antagonists & inhibitors
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Adenosine Triphosphate / biosynthesis
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Animals
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Antibodies, Monoclonal / pharmacology
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Antimetabolites, Antineoplastic / pharmacology
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B7-H1 Antigen / genetics*
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B7-H1 Antigen / immunology
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Cell Lineage / drug effects
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Cell Lineage / genetics
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Cell Lineage / immunology*
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / immunology
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Diazooxonorleucine / pharmacology
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Epoxy Compounds / pharmacology
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Gene Expression Profiling
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Gene Expression Regulation
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Glycolysis / drug effects
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Interferon-gamma / antagonists & inhibitors
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Interferon-gamma / genetics*
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Interferon-gamma / immunology
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Interleukin Receptor Common gamma Subunit / deficiency
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Interleukin Receptor Common gamma Subunit / genetics
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Interleukin Receptor Common gamma Subunit / immunology
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Lymphocyte Activation
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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Oligomycins / pharmacology
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Oxidative Phosphorylation / drug effects
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Programmed Cell Death 1 Receptor / antagonists & inhibitors
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Programmed Cell Death 1 Receptor / genetics*
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Programmed Cell Death 1 Receptor / immunology
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Receptors, Antigen, T-Cell / genetics
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Receptors, Antigen, T-Cell / immunology
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Signal Transduction
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T-Lymphocytes / cytology
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T-Lymphocytes / drug effects
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T-Lymphocytes / immunology*
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T-Lymphocytes / transplantation
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Transplantation, Homologous
Substances
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Antibodies, Monoclonal
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Antimetabolites, Antineoplastic
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B7-H1 Antigen
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Cd274 protein, mouse
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DNA-Binding Proteins
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Epoxy Compounds
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Il2rg protein, mouse
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Interleukin Receptor Common gamma Subunit
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Oligomycins
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Pdcd1 protein, mouse
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Programmed Cell Death 1 Receptor
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Rag2 protein, mouse
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Receptors, Antigen, T-Cell
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Diazooxonorleucine
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Interferon-gamma
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Adenosine Triphosphate
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etomoxir