Hashimoto et al. thoroughly review properties of exhausted CD8+ T cells, including sustained expression of inhibitory receptors, altered metabolism, unique cytokine expression profile, and a distinct epigenetic signature, with emphasis on the role of PD-1. They discuss the strategies for reinvigorating exhausted CD8+ T cells in cancer and chronic infections, the dependency on CD28, and the recently identified stem cell-like subset of PD-1+CD8+ T cells that localize in lymphoid tissue and proliferate in response to PD-1 blockade in chronic viral infections.

Antigen-specific CD8 T cells are central to the control of chronic infections and cancer, but persistent antigen stimulation results in T cell exhaustion. Exhausted CD8 T cells have decreased effector function and proliferative capacity, partly caused by overexpression of inhibitory receptors such as programmed cell death (PD)-1. Blockade of the PD-1 pathway has opened a new therapeutic avenue for reinvigorating T cell responses, with positive outcomes especially for patients with cancer. Other strategies to restore function in exhausted CD8 T cells are currently under evaluation-many in combination with PD-1-targeted therapy. Exhausted CD8 T cells comprise heterogeneous cell populations with unique differentiation and functional states. A subset of stem cell-like PD-1(+) CD8 T cells responsible for the proliferative burst after PD-1 therapy has been recently described. A greater understanding of T cell exhaustion is imperative to establish rational immunotherapeutic interventions.

Author Info: (1) Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA; email: mhashi4@emory.edu , akamphorst@emory.edu , sejin.im@emory.edu

Author Info: (1) Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA; email: mhashi4@emory.edu , akamphorst@emory.edu , sejin.im@emory.edu , karaki@emory.edu , rahmed@emory.edu. (2) Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA; email: mhashi4@emory.edu , akamphorst@emory.edu , sejin.im@emory.edu , karaki@emory.edu , rahmed@emory.edu. (3) Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA; email: mhashi4@emory.edu , akamphorst@emory.edu , sejin.im@emory.edu , karaki@emory.edu , rahmed@emory.edu. (4) Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA; email: mhashi4@emory.edu , akamphorst@emory.edu , sejin.im@emory.edu , karaki@emory.edu , rahmed@emory.edu. Department of Urology, Emory University School of Medicine, Atlanta, Georgia 30322, USA; email: haydn.kissick@emory.edu. (5) Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA; email: rnpilla@emory.edu , ssramal@emory.edu. (6) Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA; email: rnpilla@emory.edu , ssramal@emory.edu. (7) Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA; email: mhashi4@emory.edu , akamphorst@emory.edu , sejin.im@emory.edu , karaki@emory.edu , rahmed@emory.edu. (8) Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA; email: mhashi4@emory.edu , akamphorst@emory.edu , sejin.im@emory.edu , karaki@emory.edu , rahmed@emory.edu.

Less