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 remains unclear. In addition to its expected role in restraining clonal effector expansion, here we show that 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 pre-existing 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 bioenergetics needs of quiescent memory. These results define PD-1 as a key metabolic regulator of protective T cell immunity. Further, these results have potential clinical implications for pre-existing CD8 T cell memory during PD-1 checkpoint blockade immunotherapy. We used genomewide microarrays to analyze the mRNA gene expression profile of LCMV GP33-specific effector CD8 T cells from P14 mice that were differentiated in the presence (WT) or absence of PD1 signals (PD1KO) upon in vivo infection with LCMV Armstrong. 4 Groups of FACS purified GP33-specific CD8 T cells were analyzed by Affymetrix microarrays. Group 1 - Naïve Wild Type GP33-specific CD8 T cells from P14 mice; Group 2 - Wild type GP33-specific CD8 T cells isolated at Day 7 post-infection from LCMV Arm infected mice; Group 3 - PD1 Knockout GP33-specific CD8 T cells isolated at Day 7 post-infection from LCMV Arm infected mice; Group 4 - Memory Wild type GP33-specific CD8 T cells isolated at Day >90 post-infection from LCMV Arm infected mice