Metabolic plasticity of human T cells: Preserved cytokine production under glucose deprivation or mitochondrial restriction, but 2‐deoxy‐glucose affects effector functions

• Published in: European journal of immunology 2015-09, Vol.45 (9), p.2504-2516
• Main Authors: Renner, Kathrin, Geiselhöringer, Anna‐Lena, Fante, Matthias, Bruss, Christina, Färber, Stephanie, Schönhammer, Gabriele, Peter, Katrin, Singer, Katrin, Andreesen, Reinhard, Hoffmann, Petra, Oefner, Peter, Herr, Wolfgang, Kreutz, Marina
• Format: Article
• Language: English
• Subjects: 2‐deoxy‐glucose; ATP; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Proliferation - drug effects; Cytokines; Deoxyglucose - pharmacology; Glucose - deficiency; Glucose deprivation; Glycolysis - drug effects; Human CD4 T cells; Human CD8 T cells; Humans; Interferon-gamma - biosynthesis; Interferon-gamma - immunology; Interleukin-10 - biosynthesis; Interleukin-10 - immunology; Interleukin-2 - biosynthesis; Interleukin-2 - immunology; Interleukin-4 - biosynthesis; Interleukin-4 - immunology; Lymphocytes; Metabolism; Mitochondria - drug effects; Mitochondria - immunology; Mitochondria - metabolism; Mitochondrial inhibition; Monocytes - cytology; Monocytes - drug effects; Monocytes - immunology; Monocytes - metabolism; Oxidative Phosphorylation - drug effects; Primary Cell Culture; Respiration; T cell receptors; T-Lymphocyte Subsets - cytology; T-Lymphocyte Subsets - drug effects; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - immunology
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201545473

The strong link between T‐cell metabolism and effector functions is well characterized in the murine system but hardly investigated in human T cells. Therefore, we analyzed glycolytic and mitochondrial activity in correlation to function in activated human CD4 and CD8 T cells. Glycolysis was barely detectable upon stimulation but accelerated beyond 24 h, whereas mitochondrial activity was elevated immediately in both T‐cell populations. Glucose deprivation or mitochondrial restriction reduced proliferation, had only a transient impact on “on‐blast formation” and no impact on viability, IFN‐γ, IL‐2, IL‐4, and IL‐10 production, whereas TNF was reduced. Similar results were obtained in bulk T cells and T‐cell subsets. Elevated respiration under glucose restriction demonstrated metabolic flexibility. Administration of the glycolytic inhibitor 2‐deoxy‐glucose suppressed both glycolysis and respiration and exerted a strong impact on cytokine production that persisted for IFN‐γ after removal of 2‐deoxy‐glucose. Taken together, glycolytic or mitochondrial restriction alone compromised proliferation of human T cells, but barely affected their effector functions. In contrast, effector functions were severely affected by 2‐deoxy‐glucose treatment.