Metabolic regulation by PD-1 signaling promotes long-lived quiescent CD8 T cell memory in mice

Inhibitory signaling in dysfunctional CD8 T cells through the programmed cell death 1 (PD-1) axis is well established in chronic viral infections and cancers. PD-1 is also transiently induced to high concentrations during priming of acute infections and immunizations, yet its impact on the development of long-lived antigen-independent T cell memory remainsunclear. In additionto its expectedrole in restraining clonaleffector expansion, here,weshowthat PD-1 expression on antigen-specific CD8 T cells is required for the development of a durable CD8 T cell memory pool after antigen clearance. Loss of T cell-specific PD-1 signaling led to increased contraction and a defect in antigen-independent renewal of memory CD8 T cells in response to homeostatic cytokine signals, thus resulting in attrition of the memory pool over time. Whereas exhausted CD8 T cells regain function after PD-1 checkpoint blockade during chronic viral infection, the preexisting pool of resting functional bystander memory CD8 T cells established in response to a previously administered immunogen decreased. Metabolically, PD-1 signals were necessary for regulating the critical balance of mTOR-dependent anabolic glycolysis and fatty acid oxidation programs to meet the bioenergetic needs of quiescent CD8 T cell memory. These results define PD-1 as a key metabolic regulator of protective T cell immunity. Furthermore, these results have potential clinical implications for preexisting CD8 T cell memory during PD-1 checkpoint blockade therapy.

Automated summary

The inhibitory role of PD-1 signaling in CD8 T cells has been well established in chronic viral infections and cancers, but its impact on the development of long-lived antigen-independent T cell memory remains unclear. Studies have shown that PD-1 expression on antigen-specific CD8 T cells is essential for the formation of a durable CD8 T cell memory pool, with loss of T cell-specific PD-1 signaling leading to increased apoptosis and a defect in antigen-independent renewal of memory CD8 T cells.