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

• Published in: The Journal of experimental medicine Vol. 209; no. 13; pp. 2485 - 2499
• Main Authors: Frebel, Helge, Nindl, Veronika, Schuepbach, Reto A., Braunschweiler, Thomas, Richter, Kirsten, Vogel, Johannes, Wagner, Carsten A., Loffing-Cueni, Dominique, Kurrer, Michael, Ludewig, Burkhard, Oxenius, Annette
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 17.12.2012
• Subjects: Animals; B7-H1 Antigen - deficiency; B7-H1 Antigen - genetics; B7-H1 Antigen - physiology; Capillary Permeability - physiology; CD8-Positive T-Lymphocytes - immunology; Disease Models, Animal; Endothelium, Vascular - pathology; H-2 Antigens - genetics; H-2 Antigens - physiology; Histocompatibility Antigen H-2D; Hypotension - etiology; Hypotension - physiopathology; Lymphocytic Choriomeningitis - immunology; Lymphocytic Choriomeningitis - pathology; Lymphocytic Choriomeningitis - physiopathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Pore Forming Cytotoxic Proteins - deficiency; Pore Forming Cytotoxic Proteins - genetics; Pore Forming Cytotoxic Proteins - physiology; Programmed Cell Death 1 Receptor - deficiency; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - physiology; Pulmonary Edema - etiology; Pulmonary Edema - physiopathology; Shock - immunology; Shock - physiopathology; Shock - prevention & control; Signal Transduction
• ISSN: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20121015

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.