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

Frebel H, Nindl V, Schuepbach RA, Braunschweiler T, Richter K, Vogel J, Wagner CA, Loffing-Cueni D, Kurrer M, Ludewig B, Oxenius A - J. Exp. Med. (2012)

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Microbiology, ETH Zurich, 8093 Zurich, Switzerland.

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.

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PD-1 KO mice develop fatal CD8 T cell–dependent pathology during early systemic LCMV infection. (A) PD-1 KO mice were infected with 106 pfu LCMV clone 13, 106 pfu LCMV docile, or 102 pfu LCMV docile and monitored for morbidity (hunched back, ruffled fur, and reduced motoric activity). (B and C) Core temperatures were measured in WT and PD-1 KO mice (B), untreated and αPD-L1–treated WT mice (C). (D) Morbidity was monitored in undepleted and CD8 T cell– or CD4 T cell–depleted PD-1 KO mice at the indicated times after infection with 106 pfu LCMV docile. (E) Cytokine concentrations in the sera of WT and PD-1 KO mice were analyzed on day 6 after 106 pfu LCMV docile infection. A–E: n = 3–4 mice per group. Means ± SEM from one representative of two experiments are shown. (F) Liver AST concentrations in the sera of WT and PD-1 KO mice were determined on day 6 after infection. WT, n = 8 mice; KO, n = 7 mice. Means ± SEM from two pooled experiments are shown. *, P < 0.05; **, P < 0.01 (unpaired two-tailed Student’s t test).
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fig1: PD-1 KO mice develop fatal CD8 T cell–dependent pathology during early systemic LCMV infection. (A) PD-1 KO mice were infected with 106 pfu LCMV clone 13, 106 pfu LCMV docile, or 102 pfu LCMV docile and monitored for morbidity (hunched back, ruffled fur, and reduced motoric activity). (B and C) Core temperatures were measured in WT and PD-1 KO mice (B), untreated and αPD-L1–treated WT mice (C). (D) Morbidity was monitored in undepleted and CD8 T cell– or CD4 T cell–depleted PD-1 KO mice at the indicated times after infection with 106 pfu LCMV docile. (E) Cytokine concentrations in the sera of WT and PD-1 KO mice were analyzed on day 6 after 106 pfu LCMV docile infection. A–E: n = 3–4 mice per group. Means ± SEM from one representative of two experiments are shown. (F) Liver AST concentrations in the sera of WT and PD-1 KO mice were determined on day 6 after infection. WT, n = 8 mice; KO, n = 7 mice. Means ± SEM from two pooled experiments are shown. *, P < 0.05; **, P < 0.01 (unpaired two-tailed Student’s t test).

Mentions: A previous study indicated a lethal outcome of systemic LCMV infection in PD-L1–deficient mice (Barber et al., 2006). To confirm that this fatal pathology was the result of deficient signaling via the PD-1–PD-L1 pathway, we examined the course of systemic LCMV infection in PD-1 (receptor) KO mice. As reported for PD-L1 KO mice, PD-1 KO mice also succumbed to a systemic LCMV clone 13 infection (106 pfu) with similar kinetics (Fig. 1 A). This also applied to a systemic infection (106 pfu) with the more virulent strain LCMV docile. In contrast, PD-1 KO mice did not succumb to a rapidly controlled LCMV infection when infected with 102 pfu of LCMV docile. Thus, lethal pathology only developed during a systemic infection which, in the following experiments, was established by infecting with 106 pfu of LCMV docile.


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

Frebel H, Nindl V, Schuepbach RA, Braunschweiler T, Richter K, Vogel J, Wagner CA, Loffing-Cueni D, Kurrer M, Ludewig B, Oxenius A - J. Exp. Med. (2012)

PD-1 KO mice develop fatal CD8 T cell–dependent pathology during early systemic LCMV infection. (A) PD-1 KO mice were infected with 106 pfu LCMV clone 13, 106 pfu LCMV docile, or 102 pfu LCMV docile and monitored for morbidity (hunched back, ruffled fur, and reduced motoric activity). (B and C) Core temperatures were measured in WT and PD-1 KO mice (B), untreated and αPD-L1–treated WT mice (C). (D) Morbidity was monitored in undepleted and CD8 T cell– or CD4 T cell–depleted PD-1 KO mice at the indicated times after infection with 106 pfu LCMV docile. (E) Cytokine concentrations in the sera of WT and PD-1 KO mice were analyzed on day 6 after 106 pfu LCMV docile infection. A–E: n = 3–4 mice per group. Means ± SEM from one representative of two experiments are shown. (F) Liver AST concentrations in the sera of WT and PD-1 KO mice were determined on day 6 after infection. WT, n = 8 mice; KO, n = 7 mice. Means ± SEM from two pooled experiments are shown. *, P < 0.05; **, P < 0.01 (unpaired two-tailed Student’s t test).
© Copyright Policy - openaccess
Related In: Results  -  Collection

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fig1: PD-1 KO mice develop fatal CD8 T cell–dependent pathology during early systemic LCMV infection. (A) PD-1 KO mice were infected with 106 pfu LCMV clone 13, 106 pfu LCMV docile, or 102 pfu LCMV docile and monitored for morbidity (hunched back, ruffled fur, and reduced motoric activity). (B and C) Core temperatures were measured in WT and PD-1 KO mice (B), untreated and αPD-L1–treated WT mice (C). (D) Morbidity was monitored in undepleted and CD8 T cell– or CD4 T cell–depleted PD-1 KO mice at the indicated times after infection with 106 pfu LCMV docile. (E) Cytokine concentrations in the sera of WT and PD-1 KO mice were analyzed on day 6 after 106 pfu LCMV docile infection. A–E: n = 3–4 mice per group. Means ± SEM from one representative of two experiments are shown. (F) Liver AST concentrations in the sera of WT and PD-1 KO mice were determined on day 6 after infection. WT, n = 8 mice; KO, n = 7 mice. Means ± SEM from two pooled experiments are shown. *, P < 0.05; **, P < 0.01 (unpaired two-tailed Student’s t test).
Mentions: A previous study indicated a lethal outcome of systemic LCMV infection in PD-L1–deficient mice (Barber et al., 2006). To confirm that this fatal pathology was the result of deficient signaling via the PD-1–PD-L1 pathway, we examined the course of systemic LCMV infection in PD-1 (receptor) KO mice. As reported for PD-L1 KO mice, PD-1 KO mice also succumbed to a systemic LCMV clone 13 infection (106 pfu) with similar kinetics (Fig. 1 A). This also applied to a systemic infection (106 pfu) with the more virulent strain LCMV docile. In contrast, PD-1 KO mice did not succumb to a rapidly controlled LCMV infection when infected with 102 pfu of LCMV docile. Thus, lethal pathology only developed during a systemic infection which, in the following experiments, was established by infecting with 106 pfu of LCMV docile.

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Microbiology, ETH Zurich, 8093 Zurich, Switzerland.

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.

Show MeSH
Related in: MedlinePlus