title: Programmed death 1 protects from fatal circulatory failure during systemic virus infection of mice.
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.
authors.affiliation: Institute of Microbiology, ETH Zurich, 8093 Zurich, Switzerland.
authors.forename: Helge
authors.initials: H
authors.lastname: Frebel
authors.forename: Veronika
authors.initials: V
authors.lastname: Nindl
authors.forename: Reto A
authors.initials: RA
authors.lastname: Schuepbach
authors.forename: Thomas
authors.initials: T
authors.lastname: Braunschweiler
authors.forename: Kirsten
authors.initials: K
authors.lastname: Richter
authors.forename: Johannes
authors.initials: J
authors.lastname: Vogel
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Wagner
authors.forename: Dominique
authors.initials: D
authors.lastname: Loffing-Cueni
authors.forename: Michael
authors.initials: M
authors.lastname: Kurrer
authors.forename: Burkhard
authors.initials: B
authors.lastname: Ludewig
authors.forename: Annette
authors.initials: A
authors.lastname: Oxenius
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002199:Capillary Permeability / Q000502:physiology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000473:pathology; D006183:H-2 Antigens / Q000235:genetics / Q000502:physiology; D064532:Histocompatibility Antigen H-2D; D007022:Hypotension / Q000209:etiology / Q000503:physiopathology; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D052899:Pore Forming Cytotoxic Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D061026:Programmed Cell Death 1 Receptor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011654:Pulmonary Edema / Q000209:etiology / Q000503:physiopathology; D012769:Shock / Q000276:immunology / Q000503:physiopathology* / Q000517:prevention & control; D015398:Signal Transduction
chemical_list: D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; C491383:Pdcd1 protein, mouse; D052899:Pore Forming Cytotoxic Proteins; D061026:Programmed Cell Death 1 Receptor; C483886:perforin, mouse