Ketolysis drives CD8⁺ T cell effector function through effects on histone acetylation.

Area of Science:

• Immunology
• Metabolic pathways
• Cellular metabolism

Background:

• T cell metabolism is influenced by nutrient availability, affecting immune responses.
• Ketone bodies (KBs) are metabolic byproducts with potential roles in immune cell function.

Purpose of the Study:

• To investigate the role of ketone bodies (KBs) as fuels for CD8+ T cell metabolism and effector functions.
• To elucidate the mechanisms by which KBs impact CD8+ T cell responses.

Main Methods:

• In vitro and in vivo studies assessing CD8+ T cell metabolism and function.
• Analysis of KB utilization and its impact on cytokine production and cytolytic activity.
• Investigation of KB effects on the tricarboxylic acid (TCA) cycle and histone acetylation.

Main Results:

• Ketone bodies (KBs), including β-hydroxybutyrate (βOHB) and acetoacetate (AcAc), are essential fuels for CD8+ T cell metabolism and effector function.
• βOHB enhances CD8+ T effector (Teff) cell cytokine production and cytolytic activity.
• KB oxidation (ketolysis) is required for Teff cell responses to bacterial infection and tumor challenge.
• CD8+ Teff cells preferentially utilize KBs over glucose for TCA cycle fueling.
• KBs increase respiratory capacity and TCA cycle-dependent pathways in CD8+ T cells.
• βOHB serves as a key substrate for acetyl-CoA production, influencing histone acetylation and effector responses.

Conclusions:

• Cell-intrinsic ketolysis is a critical metabolic and epigenetic driver of optimal CD8+ T cell effector responses.
• Ketone bodies represent a significant nutrient source that enhances cellular immunity.