Ketone Bodies Improve Human CD8+ Cytotoxic T-Cell Immune Response During COVID-19 Infection

Abstract

Severe COVID-19 is characterized by profound CD8+ T-cell dysfunction, which cannot be specifically treated to date. We here investigate whether metabolic CD8+ T-cell reprogramming by ketone bodies could be a promising strategy to overcome the immunoparalysis in COVID-19 patients. This approach was triggered by our recent pioneering study, which has provided evidence that CD8+ T-cell capacity in healthy subjects could be significantly empowered by a Ketogenic Diet. These improvements were achieved by immunometabolic rewiring toward oxidative phosphorylation. We here report similar strengthening of CD8+ T cells obtained from severely diseased COVID-19 patients: Flow cytometry and ELISA revealed elevated cytokine expression and secretion (up to + 24%) upon ketone treatment and enhanced cell lysis capacity (+ 21%). Metabolic analyses using Seahorse technology revealed upregulated mitochondrial respiratory chain activity (+ 25%), enabling both superior energy supply (+ 44%) and higher mitochondrial reactive oxygen species signaling. These beneficial effects of ketones might represent evolutionary conserved mechanisms to strengthen human immunity. Our findings pave the road for metabolic treatment studies in COVID-19.

Tumor acidity: From hallmark of cancer to target of treatment

“…It is important to note that human glucose levels may be reduced to very low levels without causing harm ( 111 ), and ketone bodies can be used for energy production with benefits for the organism ( 112 , 113 ). For instance, a ketogenic diet improves the function of T cells ( 114 , 115 ) and possibly creates an unfavorable metabolic environment for cancer cells ( 116 , 117 ). However, ketone bodies utilization or formation may be a promoter for tumor cells proliferation and metastasis ( 118 – 121 ).…”

Ketolysis is a metabolic driver of CD8+ T cell effector function through histone acetylation

“…We speculate that ketolysis evolved as a metabolic program to preserve T cell effector function during periods of starvation or inflammation-driven changes in feeding behavior (52). While immunomodulatory effects of KBs on immune cell populations have been documented (17,35,(53)(54)(55), our results point towards ketolysis-driven acetyl-CoA synthesis as a key mechanism underlying the immunomodulatory effects bOHB on T cell function. We establish that bOHB is a major source of acetyl-CoA production in CD8 + T cells, which directly contributes to histone acetylation, and promotes permissive H3K27 acetylation at effector gene loci (i.e., Ifng, Gzmb, Tbx21) in activated CD8 + T cells.…”

Foods may modify responsiveness to cancer immune checkpoint blockers by altering both the gut microbiota and activation of estrogen receptors in immune cells

“…In addition to fecal SCFA production, an increase ketone bodies in the liver, as a result of ketogenic condition caused for example by ketogenic diet or fasting, might be most effective method to increase the proportion of patients who respond to ICB therapy. Ketone bodies bind and activate SCFA receptors in immune cells, resulting activation of CD8+ T cells (Polanczyk et al, 2006;Hirschberger et al, 2022).…”

“…Normally, serum acetate levels are higher than AcAc levels, but during ketogenic conditions both AcAc and 3HB are markedly increased, while SCFAs are dropped by several folds (Miyamoto et al, 2019). These ketone bodies then bind to SCFA receptors GPR41, GPR43 and GPR109A (Kimura et al, 2011;Offermanns, 2017;Miyamoto et al, 2019), and can improve anti-tumor immune responses (Hirschberger et al, 2022).…”

“…Since caloric restriction induces a ketogenic condition, it elevates circulating ketone bodies (Miyamoto et al, 2019). Thus, caloric restriction might improve ICB response via an increase in ketone bodies and/or by reducing circulating E2 levels and E2 in the TME, both of which lead to improved CD8+ T cell activity (Hirschberger et al, 2022).…”