Helge Frebel 1 , Veronika Nindl 2 , Reto A. Schuepbach 3 , Thomas Braunschweiler 1 , Kirsten Richter 1 , Johannes Vogel 4 , Carsten A. Wagner 5 , Dominique Loffing-Cueni 6 , Michael Kurrer 7 , 8 , Burkhard Ludewig 2 , Annette Oxenius , 1
17 December 2012
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.
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.