Kalia et al. investigated the role of PD-1 signaling in the formation of effector and memory CD8+ T cell responses after infection. During acute infection, a lack of or blockade of PD-1 on CD8+ T cells did not substantially impact activation, proliferation, or effector differentiation. However, for memory responses, apoptosis signatures and contraction increased in the absence of PD-1 signaling, resulting in a decline of long-term memory CD8+ T cells after infection. These PD-1-lacking T cells had higher aerobic glycolysis and impaired fatty acid oxidation, suggesting that PD-1 plays a role in establishing long-term homeostatic maintenance in CD8+ T memory cells.
Contributed by Maartje Wouters
ABSTRACT: 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
Author Info: (1) Division of Hematology and Oncology, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA. Ben Towne Center for Childhood Cancer Resear
Author Info: (1) Division of Hematology and Oncology, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA. Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA 98101, USA. (2) Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA 98101, USA. (3) Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA 98101, USA. (4) Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA 98101, USA. (5) QIAGEN Sciences LLC, 19300 Germantown Rd, Germantown, MD 20874, USA. (6) Elucidata, Cambridge, MA 02139, USA. (7) Dermatology Division, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. (8) Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA. Department of Global Health, University of Washington School of Medicine, Seattle, WA 98195, USA. (9) Elucidata, Cambridge, MA 02139, USA. (10) Dermatology Division, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. (11) Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. (12) Division of Hematology and Oncology, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA. Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA 98101, USA. Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA.
