Metabolic reprogramming driven by Ant2 deficiency augments T Cell function and anti-tumor immunity in mice

Area of Science:

• Immunology
• Cellular Metabolism
• Mitochondrial Biology

Background:

• T cell activation demands significant NAD+ production, often surpassing oxidative phosphorylation (OXPHOS) capacity.
• ADP/ATP translocase-2 (Ant2) facilitates mitochondrial-cytoplasmic ADP/ATP exchange, crucial for cellular energy homeostasis.

Purpose of the Study:

• To investigate the role of Ant2 in T cell metabolic adaptation during activation.
• To explore the therapeutic potential of targeting Ant2 in T cell-mediated immunity.

Main Methods:

• Generation of T cell-specific Ant2 knockout (Ant2-/-) mice.
• Metabolic profiling and functional assays of wild-type and Ant2-/- T cells.
• Pharmacological inhibition of ANT in wild-type T cells and evaluation in cancer models.

Main Results:

• Ant2 deficiency restricts OXPHOS, limiting NAD+ regeneration but enhancing T cell activation, proliferation, and effector functions.
• Ant2-/- T cells exhibit an activated metabolic phenotype with increased mitobiogenesis and anabolism.
• Pharmacological ANT inhibition in wild-type T cells mimicked the Ant2-/- phenotype and improved adoptive T cell therapy efficacy.

Conclusions:

• Ant2-deficient T cells bypass typical metabolic reprogramming, leading to enhanced function.
• Targeting ANT presents a potential strategy for immune modulation and improving cancer immunotherapy.