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 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.
Merkel cell carcinoma can be indolent: A case with 7 locoregional recurrences over 15 years highlights the importance of patient-tailored management
Patients who experience a recurrence of their Merkel cell carcinoma are often treated aggressively. We report a case of a man with an unusually long course of MCC over 15 years who had his MCC recur around his face or neck 7 times before eventually developing distant spread. Because he had 4 major medical problems at the time his MCC initially appeared, less aggressive therapies were chosen for his recurrences, and there was no evidence of disease for the vast majority of his 15-year course, during which he enjoyed excellent quality of life. This case emphasizes the importance of customizing care in MCC to give patients the best quality and quantity of life possible in their particular situation.