{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T05:01:08Z","timestamp":1792904468948,"version":"4.5.0"},"reference-count":70,"publisher":"Rockefeller University Press","issue":"13","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,12,17]]},"abstract":"<jats:p>The inhibitory programmed death 1 (PD-1)\u2013programmed 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\u2013PD-L1\u2013mediated inhibition is considered as a therapeutic approach to reinvigorate antiviral T cell responses. Yet previous studies reported that PD-L1\u2013deficient 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\u2013PD-L1 signaling or lacking PD-1 signaling in CD8 T cells succumbed to fatal CD8 T cell\u2013mediated 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\u2013PD-L1 pathway protects the vascular system from severe CD8 T cell\u2013mediated 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\u2013PD-L1 pathway during systemic virus infections.<\/jats:p>","DOI":"10.1084\/jem.20121015","type":"journal-article","created":{"date-parts":[[2012,12,10]],"date-time":"2012-12-10T22:58:10Z","timestamp":1355180290000},"page":"2485-2499","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":203,"title":["Programmed death 1 protects from fatal circulatory failure during systemic virus infection of mice"],"prefix":"10.1084","volume":"209","author":[{"given":"Helge","family":"Frebel","sequence":"first","affiliation":[{"name":"Institute of Microbiology, ETH Zurich, 8093 Zurich, Switzerland 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronika","family":"Nindl","sequence":"additional","affiliation":[{"name":"Institute of Immunobiology, Cantonal Hospital St. Gallen, 9007 St. Gallen, Switzerland 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reto A.","family":"Schuepbach","sequence":"additional","affiliation":[{"name":"Surgical Intensive Care Medicine, University Hospital Zurich, 8091 Zurich, Switzerland 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Braunschweiler","sequence":"additional","affiliation":[{"name":"Institute of Microbiology, ETH Zurich, 8093 Zurich, Switzerland 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsten","family":"Richter","sequence":"additional","affiliation":[{"name":"Institute of Microbiology, ETH Zurich, 8093 Zurich, Switzerland 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Vogel","sequence":"additional","affiliation":[{"name":"Institute of Veterinary Physiology 4 , 5 , and 6 , 7"},{"name":"Institute of Physiology 4 , 5 , and 6 , 7"},{"name":"Institute of Anatomy 4 , 5 , and 6 , 7"},{"name":"University of Zurich, 8006 Zurich, Switzerland 4 , 5 , and 6 , 7"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten A.","family":"Wagner","sequence":"additional","affiliation":[{"name":"Institute of Veterinary Physiology 4 , 5 , and 6 , 7"},{"name":"Institute of Physiology 4 , 5 , and 6 , 7"},{"name":"Institute of Anatomy 4 , 5 , and 6 , 7"},{"name":"University of Zurich, 8006 Zurich, Switzerland 4 , 5 , and 6 , 7"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Loffing-Cueni","sequence":"additional","affiliation":[{"name":"Institute of Veterinary Physiology 4 , 5 , and 6 , 7"},{"name":"Institute of Physiology 4 , 5 , and 6 , 7"},{"name":"Institute of Anatomy 4 , 5 , and 6 , 7"},{"name":"University of Zurich, 8006 Zurich, Switzerland 4 , 5 , and 6 , 7"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Kurrer","sequence":"additional","affiliation":[{"name":"Institute of Veterinary Physiology 4 , 5 , and 6 , 7"},{"name":"Institute of Physiology 4 , 5 , and 6 , 7"},{"name":"Institute of Anatomy 4 , 5 , and 6 , 7"},{"name":"University of Zurich, 8006 Zurich, Switzerland 4 , 5 , and 6 , 7"},{"name":"Institute of Pathology Enge, 8027 Zurich, Switzerland 8"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Burkhard","family":"Ludewig","sequence":"additional","affiliation":[{"name":"Institute of Immunobiology, Cantonal Hospital St. Gallen, 9007 St. Gallen, Switzerland 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette","family":"Oxenius","sequence":"additional","affiliation":[{"name":"Institute of Microbiology, ETH Zurich, 8093 Zurich, Switzerland 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2012,12,10]]},"reference":[{"key":"2023072600473063000_bib1","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1126\/science.274.5284.94","article-title":"Phenotypic analysis of antigen-specific T lymphocytes","volume":"274","author":"Altman","year":"1996","journal-title":"Science."},{"key":"2023072600473063000_bib2","doi-asserted-by":"publisher","first-page":"2355","DOI":"10.1084\/jem.20100124","article-title":"Pathogenic virus-specific T cells cause disease during treatment with the calcineurin inhibitor FK506: implications for transplantation","volume":"207","author":"Araki","year":"2010","journal-title":"J. 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