In response to KD, increased mitochondrial mass, ETC complex formation, aerobic oxidative phosphorylation capacity and -tightly controlled- ROS production was identified in human T cells.Additionally, KD also enhanced regulatory T cell abundance and function, and primed human T cells to memory cell formation.KD augmented human CD4 + and CD8 + T cell cytokine production and cell lysis capacity in vitro and in vivo.This study identifies KD as a potent nutritional immunometabolic intervention to reprogram human T cell immunometabolism, favouring mitochondrial oxidative phosphorylation, thus enhancing both effector and regulatory T cell immune capacity and priming human T cells towards memory cell formation. Ketogenic diet (KD) is characterized by a very limited uptake of carbohydrates, resulting in endogenous production of ketone bodies. Rethinking the value of nutrition and dietary interventions in modern medicine is required. Our data suggest a very-low-carbohydrate diet as a clinical tool to improve human T-cell immunity. This confers superior respiratory reserve, cellular energy supply, and reactive oxygen species signaling. RNAseq and functional metabolic analyses revealed a fundamental immunometabolic reprogramming in response to ketones favoring mitochondrial oxidative metabolism. CD4 +, CD8 +, and regulatory T-cell capacity were markedly enhanced, and T memory cell formation was augmented. We show that ketone bodies profoundly impact human T-cell responses. We have investigated this topic in an in vitro model using primary human T cells and in an immuno-nutritional intervention study enrolling healthy volunteers. There are as yet unproven assumptions that ketone bodies positively affect human immunity. Very-low-carbohydrate diet triggers the endogenous production of ketone bodies as alternative energy substrates. 6 Department of Radiation Oncology, LMU University Hospital, Ludwig-Maximilian-University München (LMU), Munich, Germany.5 Helmholtz Center Munich, Research Unit Radiation Cytogenetics, Neuherberg, Germany.4 Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilian-University München (LMU), Munich, Germany.3 Department of Anesthesia, Intensive Care Medicine and Pain Therapy, University Hospital Knappschaftskrankenhaus Bochum, Bochum, Germany.2 Department of Anaesthesiology and Intensive Care Medicine, Research Unit Molecular Medicine, LMU University Hospital, Ludwig-Maximilian-University München (LMU), Munich, Germany.1 Walter Brendel Center of Experimental Medicine, Ludwig-Maximilian-University München (LMU), Munich, Germany.
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