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Nature. 2016 Sep 15;537(7620):417-421. doi: 10.1038/nature19330. Epub 2016 Aug 2.

Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy.

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Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-0421, USA.
Department of Immunology, University of Washington School of Medicine, Seattle, Washington 98109, USA.
Department of Urology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
School of Pharmaceutical Sciences, University of São Paulo, São Paulo 05508, Brazil.
Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
Department of Microbiology and Immunology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
Interdisciplinary Immunology Graduate Program, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.


Chronic viral infections are characterized by a state of CD8+ T-cell dysfunction that is associated with expression of the programmed cell death 1 (PD-1) inhibitory receptor. A better understanding of the mechanisms that regulate CD8+ T-cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8+ T cells. Here we identify a population of virus-specific CD8+ T cells that proliferate after blockade of the PD-1 inhibitory pathway in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). These LCMV-specific CD8+ T cells expressed the PD-1 inhibitory receptor, but also expressed several costimulatory molecules such as ICOS and CD28. This CD8+ T-cell subset was characterized by a unique gene signature that was related to that of CD4+ T follicular helper (TFH) cells, CD8+ T cell memory precursors and haematopoietic stem cell progenitors, but that was distinct from that of CD4+ TH1 cells and CD8+ terminal effectors. This CD8+ T-cell population was found only in lymphoid tissues and resided predominantly in the T-cell zones along with naive CD8+ T cells. These PD-1+CD8+ T cells resembled stem cells during chronic LCMV infection, undergoing self-renewal and also differentiating into the terminally exhausted CD8+ T cells that were present in both lymphoid and non-lymphoid tissues. The proliferative burst after PD-1 blockade came almost exclusively from this CD8+ T-cell subset. Notably, the transcription factor TCF1 had a cell-intrinsic and essential role in the generation of this CD8+ T-cell subset. These findings provide a better understanding of T-cell exhaustion and have implications in the optimization of PD-1-directed immunotherapy in chronic infections and cancer.

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