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

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 and Michael Berger ()
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Omri Yosef: Faculty of Medicine, The Hebrew University of Jerusalem
Leonor Cohen-Daniel: Faculty of Medicine, The Hebrew University of Jerusalem
Oded Shamriz: Faculty of Medicine, The Hebrew University of Jerusalem
Zahala Bar-On: Faculty of Medicine, The Hebrew University of Jerusalem
Wajeeh Salaymeh: Faculty of Medicine, The Hebrew University of Jerusalem
Amijai Saragovi: Faculty of Medicine, The Hebrew University of Jerusalem
Ifat Abramovich: Technion - Israel Institute of Technology
Bella Agranovich: Technion - Israel Institute of Technology
Veronika Lutz: Philipps University of Marburg
Joseph Tam: The Hebrew University of Jerusalem
Anna Permyakova: The Hebrew University of Jerusalem
Eyal Gottlieb: University of Texas MD Anderson Cancer Center
Magdalena Huber: Philipps University of Marburg
Michael Berger: Faculty of Medicine, The Hebrew University of Jerusalem

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59310-3

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