Pannexin-1 channels promotes CD8+ T cell effector and memory responses through distinct metabolic pathways.

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). Here, we report that T cell-specific Panx1 is needed for efficient CD8+ T cell responses to viral infection and cancer. Panx1 favors both the expansion of effector CD8+ T cells and the survival of memory CD8+ T cells. Our data suggests that, while memory CD8+ T cells require Panx1 for mitochondrial function, Panx1 promotes the glycolytic pathway in effector CD8+ T cells. Panx1 promotes memory CD8+ T cell survival together with the eATP sensor P2RX7. However, Panx1 induces effector CD8+ T cells independently of eATP. Rather, we found an unexpected link between Panx1, sodium lactate export and the activation of effector CD8+ T cells. Therefore, Panx1 regulates effector and memory CD8+ T cells through export of distinct metabolites and by engaging different intracellular pathways. Overall design: WT CD8 T cells versus Panx1-KO (KO) CD8 T cells, antigen-specific (gp33-tetramer+), sorted from mice infected with LCMV-Armstrong at d7 post-infection; terminal effectors (TE; CD127-KLRG1+) and memory precursors (MP; CD127+KLRG1-) were separated; three replicates each sample.