Very‐low‐carbohydrate diet enhances human T‐cell immunity through immunometabolic reprogramming

• Published in: EMBO molecular medicine Vol. 13; no. 8; pp. e14323 - n/a
• Main Authors: Hirschberger, Simon, Strauß, Gabriele, Effinger, David, Marstaller, Xaver, Ferstl, Alicia, Müller, Martin B, Wu, Tingting, Hübner, Max, Rahmel, Tim, Mascolo, Hannah, Exner, Nicole, Heß, Julia, Kreth, Friedrich W, Unger, Kristian, Kreth, Simone
• Format: Journal Article
• Language: English
• Published: Frankfurt John Wiley & Sons, Inc 09.08.2021; EMBO Press; John Wiley and Sons Inc; Springer Nature
• Subjects: Analysis; Carbohydrates; CD4 antigen; CD8 antigen; Cytokines; Diet; Energy resources; Immunity; Immunity (Disease); immunometabolism; Inflammation; ketogenic diet; Ketones; Low carbohydrate diet; Lymphocytes; Lymphocytes T; Memory (Computers); metabolic therapy; Metabolism; Mitochondria; Nutrient deficiency; Nutrition research; nutritional intervention; Oxidative metabolism; Phosphorylation; Physiological aspects; Protein expression; Proteins; Reactive oxygen species; Respiration; RNA sequencing; T cells; T‐cell immunity
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.202114323

Very‐low‐carbohydrate diet triggers the endogenous production of ketone bodies as alternative energy substrates. There are as yet unproven assumptions that ketone bodies positively affect human immunity. 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. We show that ketone bodies profoundly impact human T‐cell responses. CD4+, CD8+, and regulatory T‐cell capacity were markedly enhanced, and T memory cell formation was augmented. RNAseq and functional metabolic analyses revealed a fundamental immunometabolic reprogramming in response to ketones favoring mitochondrial oxidative metabolism. This confers superior respiratory reserve, cellular energy supply, and reactive oxygen species signaling. Our data suggest a very‐low‐carbohydrate diet as a clinical tool to improve human T‐cell immunity. Rethinking the value of nutrition and dietary interventions in modern medicine is required. SYNOPSIS Ketogenic diet (KD) is characterized by a very limited uptake of carbohydrates, resulting in endogenous production of ketone bodies. 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. KD augmented human CD4+ and CD8+ T cell cytokine production and cell lysis capacity in vitro and in vivo. Additionally, KD also enhanced regulatory T cell abundance and function, and primed human T cells to memory cell formation. 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. Transcriptomic analysis revealed fundamental immunometabolic reprogramming of human CD4+ and CD8+ T cells after 3 weeks of KD. Both, elevated bioenergetic capacity and ROS ‐serving as T‐cell second messenger molecules‐ provide the immunometabolic basis for enhanced T cell immunity on a KD. Ketogenic diet (KD) is characterized by a very limited uptake of carbohydrates, resulting in endogenous production of ketone bodies. 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.