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      Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8 + T cells

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          Abstract

          Using PD-1–deficient mice and co-adoptive transfer approaches, Odorizzi et al. demonstrate that PD-1 is not required for the induction of CD8 + T cell exhaustion (T EX) in chronic LCMV infection. The absence of PD-1 leads to more cytotoxic, but terminally differentiated T EX, with compromised long-term durability. PD-1 may well serve to protect T EX from excessive overstimulation, proliferation, and terminal differentiation.

          Abstract

          Programmed Death-1 (PD-1) has received considerable attention as a key regulator of CD8 + T cell exhaustion during chronic infection and cancer because blockade of this pathway partially reverses T cell dysfunction. Although the PD-1 pathway is critical in regulating established “exhausted” CD8 + T cells (T EX cells), it is unclear whether PD-1 directly causes T cell exhaustion. We show that PD-1 is not required for the induction of exhaustion in mice with chronic lymphocytic choriomeningitis virus (LCMV) infection. In fact, some aspects of exhaustion are more severe with genetic deletion of PD-1 from the onset of infection. Increased proliferation between days 8 and 14 postinfection is associated with subsequent decreased CD8 + T cell survival and disruption of a critical proliferative hierarchy necessary to maintain exhausted populations long term. Ultimately, the absence of PD-1 leads to the accumulation of more cytotoxic, but terminally differentiated, CD8 + T EX cells. These results demonstrate that CD8 + T cell exhaustion can occur in the absence of PD-1. They also highlight a novel role for PD-1 in preserving T EX cell populations from overstimulation, excessive proliferation, and terminal differentiation.

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          Most cited references16

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          The blockade of immune checkpoints in cancer immunotherapy.

          Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
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            Lineage relationship and protective immunity of memory CD8 T cell subsets.

            Memory CD8 T cells can be divided into two subsets, central (T(CM)) and effector (T(EM)), but their lineage relationships and their ability to persist and confer protective immunity are not well understood. Our results show that T(CM) have a greater capacity than T(EM) to persist in vivo and are more efficient in mediating protective immunity because of their increased proliferative potential. We also demonstrate that, following antigen clearance, T(EM) convert to T(CM) and that the duration of this differentiation is programmed within the first week after immunization. We propose that T(CM) and T(EM) do not necessarily represent distinct subsets, but are part of a continuum in a linear naive --> effector --> T(EM) --> T(CM) differentiation pathway.
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              Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection.

              Dysfunctional CD8+ T cells present in chronic virus infections can express programmed death 1 (PD-1) molecules, and the inhibition of the engagement of PD-1 with its ligand (PD-L1) has been reported to enhance the antiviral function of these T cells. We took advantage of the wide fluctuations in levels of viremia which are typical of chronic hepatitis B virus (HBV) infection to comprehensively analyze the impact of prolonged exposure to different virus quantities on virus-specific T-cell dysfunction and on its reversibility through the blocking of the PD-1/PD-L1 pathway. We confirm that chronic HBV infection has a profound effect on the HBV-specific T-cell repertoire. Despite the use of a comprehensive panel of peptides covering all HBV proteins, HBV-specific T cells were rarely observed directly ex vivo in samples from patients with chronic infection, in contrast to those from patients with acute HBV infection. In chronic HBV infection, virus-specific T cells were detected mainly in patients with lower levels of viremia. These HBV-specific CD8+ T cells expressed PD-1, and their function was improved by the blocking of PD-1/PD-L1 engagement. Thus, a broad spectrum of anti-HBV immunity is expressed by patients with chronic HBV infection and this spectrum is proportional to HBV replication levels and can be improved by blocking the PD-1/PD-L1 pathway. This information may be useful for the design of immunotherapeutic strategies to complement and optimize available antiviral therapies.
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                Author and article information

                Journal
                J Exp Med
                J. Exp. Med
                jem
                jem
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                29 June 2015
                : 212
                : 7
                : 1125-1137
                Affiliations
                [1 ]Department of Microbiology and [2 ]Penn Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104
                [3 ]Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115
                [4 ]Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115
                [5 ]Broad Institute of MIT and Harvard, Cambridge, MA 02142
                [6 ]Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115
                Author notes
                CORRESPONDENCE E. John Wherry: wherry@ 123456mail.med.upenn.edu
                Article
                20142237
                10.1084/jem.20142237
                4493417
                26034050
                31e9a782-cd29-4170-add7-68299f0e4ec0
                © 2015 Odorizzi et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

                History
                : 1 December 2014
                : 8 May 2015
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                Medicine
                Medicine

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