Metabolic Reprogramming Driven by Ant2 Deficiency Augments T Cell Function and Anti-Tumor Immunity in Mice

Authors

Omri Yosef
Leonor Cohen-Daniel
Oded Shamriz
Zahala Bar-On
Wajeeh Salaymeh
Amijai Saragovi
Ifat Abramovich
Bella Agranovich
Veronika Lutz
Joseph Tam
Anna Permyakova
Eyal Gottlieb
Magdalena Huber
Michael Berger

Publication Date

5-8-2025

Journal

Nature Communications

DOI

10.1038/s41467-025-59310-3

PMID

40341170

PMCID

PMC12062294

PubMedCentral® Posted Date

5-8-2025

PubMedCentral® Full Text Version

Post-print

Abstract

T cell activation requires a substantial increase in NAD+ production, often exceeding the capacity of oxidative phosphorylation (OXPHOS). To investigate how T cells adapt to this metabolic challenge, we generate T cell-specific ADP/ATP translocase-2 knockout (Ant2-/-) mice. Loss of Ant2, a crucial protein mediating ADP/ATP exchange between mitochondria and cytoplasm, induces OXPHOS restriction by limiting ATP synthase activity, thereby impeding NAD+ regeneration. Interestingly, Ant2-/- naïve T cells exhibit enhanced activation, proliferation and effector functions compared to wild-type controls. Metabolic profiling reveals that these T cells adopt an activated-like metabolic program with increased mitobiogenesis and anabolism. Lastly, pharmacological inhibition of ANT in wild-type T cells recapitulates the Ant2-/- phenotype and improves adoptive T cell therapy of cancer in mouse models. Our findings thus suggest that Ant2-deficient T cells bypass the typical metabolic reprogramming required for activation, leading to enhanced T cell function and highlighting the therapeutic potential of targeting ANT for immune modulation.

Keywords

Animals, Oxidative Phosphorylation, T-Lymphocytes, Mice, Mice, Knockout, Adenine Nucleotide Translocator 2, Lymphocyte Activation, NAD, Mitochondria, Mice, Inbred C57BL, Neoplasms, Immunotherapy, Adoptive, Cell Proliferation, Female, Metabolic Reprogramming

Published Open-Access

yes

Recommended Citation

Yosef, Omri; Cohen-Daniel, Leonor; Shamriz, Oded; et al., "Metabolic Reprogramming Driven by Ant2 Deficiency Augments T Cell Function and Anti-Tumor Immunity in Mice" (2025). Faculty, Staff and Student Publications. 4453.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4453