We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Metabolic regulation by PD-1 signaling promotes long-lived quiescent CD8 T cell memory in mice.
- Authors
Kalia, Vandana; Yuzefpolskiy, Yevgeniy; Vegaraju, Adithya; Xiao, Hanxi; Baumann, Florian; Jatav, Shashank; Church, Candice; Prlic, Martin; Jha, Abhishek; Nghiem, Paul; Riddell, Stanley; Sarkar, Surojit
- Abstract
keyimage.jpg Metabolism modulates memory: CD8 T cell exhaustion, often characterized by persistent expression of the inhibitory receptor, programmed cell death protein 1 (PD-1), is a feature of cancer and chronic infections. Here, Kalia et al. investigated the impact of PD-1 signaling on memory CD8 T cells. Using an acute viral infection model, the authors showed that, although PD-1 deficiency did not substantially affect initial T cell expansion, loss of T cell–specific PD-1 resulted in depletion of the memory T cell pool. The authors then showed that PD-1 signals were necessary to suppress anabolic glycolysis and drive fatty acid oxidation, metabolic programs required for quiescent memory T cell persistence. These results implicate PD-1 as a regulator of CD8 T cell metabolism and memory, which may have clinical implications for those receiving PD-1 blockade therapy. 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.
- Subjects
METABOLIC regulation; PROGRAMMED cell death 1 receptors; FATTY acid oxidation; T cells; GLYCOLYSIS; CELL death; CELL metabolism
- Publication
Science Translational Medicine, 2021, Vol 13, Issue 615, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.aba6006