Limiting mitochondrial-derived ATP transfer to the cytosol enhances T-cell activation

T cells often encounter oxidative phosphorylation (OXPHOS) insufficiency upon activation, due to increased demands for ATP and NAD ⁺ to fuel anabolic reactions. To explore how T cells overcome this insufficiency, we indirectly restricted OXPHOS by limiting mitochondrial ATP transfer to the cytosol using a T-cell-specific ADP/ATP translocase-2 knockout (Ant2 ^-/- ) mouse. Surprisingly, these naive T cells displayed heightened responsiveness to activation, increased proliferation, elevated IFNγ production and cytotoxicity. Leveraging metabolic tracing, proteomics, and various mouse models, we mechanistically elucidated that Ant2 ^-/- T cells adopt metabolic signature resembling recently activated cells, including increased mitobiogenesis and metabolic remodeling towards anabolism. Notably, pharmacological inhibition of ANT in wild-type T cells replicated the Ant2 ^-/- phenotype. We propose that Ant2-deficiency prompts naive T cells to adopt a metabolic program akin to activated cells, allowing them to circumvent the typical metabolic reprogramming during activation, thereby enhancing T-cell function. This study elucidates the intricate interplay between T-cell metabolism and function.