Mitochondrial ATP production promotes T cell differentiation and function by regulating chromatin accessibility

Area of Science:

• Immunology
• Cellular Metabolism
• Cancer Biology

Background:

• Cytotoxic CD8+ T cells are essential for eliminating chronic infections and cancer.
• Chronic antigen exposure impairs T cell effector function despite high glycolysis.
• T cell function is bioenergetically demanding.

Purpose of the Study:

• To investigate the role of D-α-hydroxybutyrate (DAHB) in T cell effector function.
• To determine how DAHB influences cellular bioenergetics and T cell differentiation.
• To assess the impact of DAHB on anti-tumor activity.

Main Methods:

• Investigated DAHB's effect on T cell ATP production, switching from glycolysis to oxidative phosphorylation.
• Analyzed changes in AMPK phosphorylation, integrated stress response (ISR), and phosphocreatine (PCr) levels.
• Examined DAHB's impact on CD8-effector gene transcription and chromatin accessibility.
• Assessed DAHB's efficacy in vitro and in vivo anti-tumor models.

Main Results:

• DAHB acts as a signaling molecule, increasing mitochondrial ATP production and promoting oxidative phosphorylation over glycolysis.
• DAHB suppresses AMPK phosphorylation and ISR, while increasing PCr levels.
• PCr bioenergetic reserve and oxidative phosphorylation are critical for T cell effector differentiation.
• DAHB enhances CD8-effector gene transcription via ATP-dependent chromatin remodeling.
• DAHB significantly improves CD8+ T cell anti-tumor activity in vitro and in vivo.

Conclusions:

• DAHB promotes T cell effector differentiation by enhancing mitochondrial ATP production and oxidative phosphorylation.
• DAHB links cellular bioenergetics to chromatin accessibility and gene expression for effector function.
• DAHB treatment confers persistent anti-tumor effects, highlighting its therapeutic potential.