Limiting mitochondrial-derived ATP transfer to the cytosol enhances T-cell activation
Yosef, O.; Cohen-Daniel, L.; Shamriz, O.; Bar-On, Z.; Saragovi, A.; Abramovich, I.; Agranovich, B.; Lutz, V.; Tam, J.; Permyakova, A.; Gottlieb, E.; Huber, M.; Berger, M.
Show 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 generated 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, impeding NAD+ regeneration. Interestingly, Ant2-/- naive T cells exhibited enhanced activation, proliferation, and effector functions compared to wild-type controls. Metabolic profiling revealed that these cells adopt an activated-like metabolic program with increased mitobiogenesis and anabolism. Pharmacological inhibition of ANT in wild-type T cells recapitulated the Ant2-/- phenotype, and improved adoptive cell therapy of cancer. Our findings suggest that Ant2-deficient T cells bypass the typical metabolic reprogramming required for activation, leading to enhanced T-cell function. These results highlight the critical role of mitochondrial metabolism in regulating T-cell fate and underscore the therapeutic potential of targeting ANT for immune modulation.
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