Abstract
Sensing of extracellular ATP (eATP) controls CD8+ Tcell function. Their accumulation can occur through export by specialized molecules, such as the release channel Pannexin 1 (Panx1). Whether Panx1 controls CD8+ Tcell immune responses invivo, however, has not been previously addressed. Here, we report that T-cell-specific Panx1 is needed for CD8+ Tcell responses to viral infections and cancer. We found that CD8-specific Panx1 promotes both effector and memory CD8+ Tcell responses. Panx1 favors initial effector CD8+ Tcell activation through extracellular ATP (eATP) export and subsequent P2RX4 activation, which helps promote full effector differentiation through extracellular lactate accumulation and its subsequent recycling. In contrast, Panx1 promotes memory CD8+ Tcell survival primarily through ATP export and subsequent P2RX7 engagement, leading to improved mitochondrial metabolism. In summary, Panx1-mediated eATP export regulates effector and memory CD8+ Tcells through distinct purinergic receptors and different metabolic and signaling pathways.
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