101
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Programmed death 1 protects from fatal circulatory failure during systemic virus infection of mice

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          The PD-1–PD-L1 pathway inhibits perforin-mediated killing of PD-L1 + vascular endothelial cells by CD8 + T cells, thereby limiting vascular damage during systemic LCMV infection.

          Abstract

          The inhibitory programmed death 1 (PD-1)–programmed death ligand 1 (PD-L1) pathway contributes to the functional down-regulation of T cell responses during persistent systemic and local virus infections. The blockade of PD-1–PD-L1–mediated inhibition is considered as a therapeutic approach to reinvigorate antiviral T cell responses. Yet previous studies reported that PD-L1–deficient mice develop fatal pathology during early systemic lymphocytic choriomeningitis virus (LCMV) infection, suggesting a host protective role of T cell down-regulation. As the exact mechanisms of pathology development remained unclear, we set out to delineate in detail the underlying pathogenesis. Mice deficient in PD-1–PD-L1 signaling or lacking PD-1 signaling in CD8 T cells succumbed to fatal CD8 T cell–mediated immunopathology early after systemic LCMV infection. In the absence of regulation via PD-1, CD8 T cells killed infected vascular endothelial cells via perforin-mediated cytolysis, thereby severely compromising vascular integrity. This resulted in systemic vascular leakage and a consequential collapse of the circulatory system. Our results indicate that the PD-1–PD-L1 pathway protects the vascular system from severe CD8 T cell–mediated damage during early systemic LCMV infection, highlighting a pivotal physiological role of T cell down-regulation and suggesting the potential development of immunopathological side effects when interfering with the PD-1–PD-L1 pathway during systemic virus infections.

          Related collections

          Most cited references45

          • Record: found
          • Abstract: found
          • Article: not found

          Phenotypic analysis of antigen-specific T lymphocytes.

          Identification and characterization of antigen-specific T lymphocytes during the course of an immune response is tedious and indirect. To address this problem, the peptide-major histocompatability complex (MHC) ligand for a given population of T cells was multimerized to make soluble peptide-MHC tetramers. Tetramers of human lymphocyte antigen A2 that were complexed with two different human immunodeficiency virus (HIV)-derived peptides or with a peptide derived from influenza A matrix protein bound to peptide-specific cytotoxic T cells in vitro and to T cells from the blood of HIV-infected individuals. In general, tetramer binding correlated well with cytotoxicity assays. This approach should be useful in the analysis of T cells specific for infectious agents, tumors, and autoantigens.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Enhancing SIV-Specific Immunity In Vivo by PD-1 Blockade

            Chronic immunodeficiency virus infections are characterized by dysfunctional cellular and humoral antiviral immune responses. As such, immune modulatory therapies that enhance and/or restore the function of virus-specific immunity may protect from disease progression. Here, we investigate the safety and immune restoration potential of the blockade of co-inhibitory receptor programmed death-1 (PD-1) during chronic SIV infection in macaques. We demonstrate that PD-1 blockade using an antibody to PD-1 is well tolerated and results in rapid expansion of virus-specific CD8 T cells with improved functional quality. This enhanced T cell immunity was seen in the blood and also in the gut, a major reservoir of SIV infection. PD-1 blockade also resulted in proliferation of memory B cells and increases in SIV envelope-specific antibody. These improved immune responses were associated with significant reductions in plasma viral load and also prolonged the survival of SIV-infected macaques. Impressively, blockade was effective during the early (wk10) as well as late (∼wk90) phases of chronic infection even under conditions of severe lymphopenia. These results demonstrate enhancement of both cellular and humoral immune responses during a pathogenic immunodeficiency virus infection by blocking a single inhibitory pathway and identify a novel therapeutic approach for HIV/AIDS.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia.

              Bacterial infection of the mammalian bloodstream can lead to overwhelming sepsis, a potentially fatal syndrome of irreversible cardiovascular collapse (shock) and critical organ failure. Cachectin, also known as tumour necrosis factor, is a macrophage-derived peptide hormone released in response to bacterial lipopolysaccharide, and it has been implicated as a principal mediator of endotoxic shock, although its function in bacterial sepsis is not known. Anaesthetized baboons were passively immunized against endogenous cachectin and subsequently infused with an LD100 dose of live Escherichia coli. Control animals (not immunized against cachectin) developed hypotension followed by lethal renal and pulmonary failure. Neutralizing monoclonal anti-cachectin antibody fragments (F(ab')2) administered to baboons only one hour before bacterial challenge protected against shock, but did not prevent critical organ failure. Complete protection against shock, vital organ dysfunction, persistent stress hormone release and death was conferred by administration of antibodies 2 h before bacterial infusion. These results indicate that cachectin is a mediator of fatal bacteraemic shock, and suggest that antibodies against cachectin offer a potential therapy of life-threatening infection.
                Bookmark

                Author and article information

                Journal
                J Exp Med
                J. Exp. Med
                jem
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                17 December 2012
                : 209
                : 13
                : 2485-2499
                Affiliations
                [1 ]Institute of Microbiology, ETH Zurich, 8093 Zurich, Switzerland
                [2 ]Institute of Immunobiology, Cantonal Hospital St. Gallen, 9007 St. Gallen, Switzerland
                [3 ]Surgical Intensive Care Medicine, University Hospital Zurich, 8091 Zurich, Switzerland
                [4 ]Institute of Veterinary Physiology , [5 ]Institute of Physiology , and [6 ]Institute of Anatomy , [7 ]University of Zurich, 8006 Zurich, Switzerland
                [8 ]Institute of Pathology Enge, 8027 Zurich, Switzerland
                Author notes
                CORRESPONDENCE Annette Oxenius: oxenius@ 123456micro.biol.ethz.ch
                Article
                20121015
                10.1084/jem.20121015
                3526355
                23230000
                74ab9687-1976-439b-b087-9f8e0f390f55
                © 2012 Frebel 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
                : 11 May 2012
                : 13 November 2012
                Categories
                Article

                Medicine
                Medicine

                Comments

                Comment on this article