Pannexin-1 channels promote CD8⁺T cell effector and memory responses through distinct intracellular pathways

Abstract Sensing of extracellular metabolites controls CD8 + T cell function. Their accumulation can occur through export by specialized molecules, such as the release channel Pannexin-1 (Panx1). Whether Panx1 controls CD8 + T cell immune responses to antigen, however, has not been previously addressed. Here, we report that T cell-specific Panx1 is needed for CD8 + T cell responses to viral infections and cancer. We found that CD8-specific Panx1 favors memory CD8 + T cell survival primarily through ATP export and induction of mitochondrial metabolism. CD8-specific Panx1 is also crucial for the effector expansion of CD8 + T cells, however this regulation occurs independently of eATP. Instead, our results suggest a connection between Panx1-induced extracellular lactate accumulation and the complete activation of effector CD8 + T cells. In summary, Panx1 regulates effector and memory CD8 + T cells through export of distinct metabolites and by engaging different metabolic and signaling pathways.