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<p>T cell activation requires a substantial increase in NAD<sup>+</sup> 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<sup>−/−</sup>) 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<sup>+</sup> regeneration. Interestingly, Ant2<sup>−/−</sup> 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<sup>−/−</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月8日

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  • 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

摘要

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.