RGD Reference Report - Programmed death 1 protects from fatal circulatory failure during systemic virus infection of mice. - Rat Genome Database

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

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 
Citation: Frebel H, etal., J Exp Med. 2012 Dec 17;209(13):2485-99. doi: 10.1084/jem.20121015. Epub 2012 Dec 10.
RGD ID: 41410802
Pubmed: (View Article at PubMed) PMID:23230000
DOI: Full-text: 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.


Disease Annotations    

Objects Annotated

Genes (Rattus norvegicus)
Cd274  (CD274 molecule)
Pdcd1  (programmed cell death 1)

Genes (Mus musculus)
Cd274  (CD274 antigen)
Pdcd1  (programmed cell death 1)

Genes (Homo sapiens)
CD274  (CD274 molecule)
PDCD1  (programmed cell death 1)

Additional Information