Abstract:The paramyxovirus pneumonia virus of mice (PVM) is a rodent model of human respiratory syncytial virus (hRSV) pathogenesis. Here we characterized the PVM-specific CD8 ؉ T-cell repertoire in susceptible C57BL/6 mice. In total, 15 PVM-specific CD8 ؉ T-cell epitopes restricted by H-2D b and/or H-2K b were identified. These data open the door for using widely profiled, genetically manipulated C57BL/6 mice to study the contribution of epitope-specific CD8 ؉ T cells to PVM pathogenesis.
“…The numbers of IFN-␥ ϩ CD8 ϩ T cells following stimulation with the PVM immunodominant peptides L 1052-1060 ( Fig. 4B) and N 339 -347 (28) were also significantly lower in mice that received RP-002 than in vehicle recipients. IFN-␥ ϩ CD8 ϩ T cells from RP-002-treated mice compared to those from vehicle-treated mice displayed increased frequencies of IFN-␥-only producers, reduced percentages of TNF-␣ and TNF-␣/IL-2-producing cells, and fewer cells producing granzyme B (Fig.…”
Section: Tnf-␣ and Ifn-␥ Are Essential For Initiating A Cytokine Stormentioning
confidence: 93%
“…3C). When single-cell suspensions of lung cells from RP-002 recipients 5 days after PVM infection were stimulated with PVM-specific H-2 b immunodominant CD8 ϩ T cell epitopes (28), the frequency of IFN-␥ ϩ cells was not enhanced compared to that for similar cells treated with a peptide that was irrelevant to PVM infection (data not shown). Analysis of PVMspecific CD8 ϩ T cells within the draining mediastinal lymph nodes (MLN) in RP-002-treated mice on day 5 postinfection revealed significantly fewer PVM-specific CD8 ϩ T cells after stimulation with the PVM immunodominant peptide (Fig.…”
Section: Tnf-␣ and Ifn-␥ Are Essential For Initiating A Cytokine Stormentioning
confidence: 94%
“…Analysis of PVMspecific CD8 ϩ T cells within the draining mediastinal lymph nodes (MLN) in RP-002-treated mice on day 5 postinfection revealed significantly fewer PVM-specific CD8 ϩ T cells after stimulation with the PVM immunodominant peptide (Fig. 3D) (28) than for mice that received vehicle. Further, after PVM peptide stimulation, IFN-␥ ϩ CD8 ϩ T cells from RP-002 recipients had fewer singly TNF-␣-producing or dually TNF-␣/IL-2-producing cells (Fig.…”
Section: Tnf-␣ and Ifn-␥ Are Essential For Initiating A Cytokine Stormentioning
The cytokine storm is an intensified, dysregulated, tissue-injurious inflammatory response driven by cytokine and immune cell components. The cytokine storm during influenza virus infection, whereby the amplified innate immune response is primarily responsible for pulmonary damage, has been well characterized. Now we describe a novel event where virus-specific T cells induce a cytokine storm. The paramyxovirus pneumonia virus of mice (PVM) is a model of human respiratory syncytial virus (hRSV). Unexpectedly, when C57BL/6 mice were infected with PVM, the innate inflammatory response was undetectable until day 5 postinfection, at which time CD8؉ T cells infiltrated into the lung, initiating a cytokine storm by their production of gamma interferon (IFN-␥) and tumor necrosis factor alpha (TNF-␣). Administration of an immunomodulatory sphingosine-1-phosphate (S1P) receptor 1 (S1P1R) agonist significantly inhibited PVM-elicited cytokine storm by blunting the PVM-specific CD8 ؉ T cell response, resulting in diminished pulmonary disease and enhanced survival.
IMPORTANCEA dysregulated overly exuberant immune response, termed a "cytokine storm," accompanies virus-induced acute respiratory diseases (VARV), is primarily responsible for the accompanying high morbidity and mortality, and can be controlled therapeutically in influenza virus infection of mice and ferrets by administration of sphingosine-1-phosphate 1 receptor (S1P1R) agonists. Here, two novel findings are recorded. First, in contrast to influenza infection, where the cytokine storm is initiated early by the innate immune system, for pneumonia virus of mice (PVM), a model of RSV, the cytokine storm is initiated late in infection by the adaptive immune response: specifically, by virus-specific CD8 T cells via their release of IFN-␥ and TNF-␣. Blockading these cytokines with neutralizing antibodies blunts the cytokine storm and protects the host. Second, PVM infection is controlled by administration of an S1P1R agonist.
“…The numbers of IFN-␥ ϩ CD8 ϩ T cells following stimulation with the PVM immunodominant peptides L 1052-1060 ( Fig. 4B) and N 339 -347 (28) were also significantly lower in mice that received RP-002 than in vehicle recipients. IFN-␥ ϩ CD8 ϩ T cells from RP-002-treated mice compared to those from vehicle-treated mice displayed increased frequencies of IFN-␥-only producers, reduced percentages of TNF-␣ and TNF-␣/IL-2-producing cells, and fewer cells producing granzyme B (Fig.…”
Section: Tnf-␣ and Ifn-␥ Are Essential For Initiating A Cytokine Stormentioning
confidence: 93%
“…3C). When single-cell suspensions of lung cells from RP-002 recipients 5 days after PVM infection were stimulated with PVM-specific H-2 b immunodominant CD8 ϩ T cell epitopes (28), the frequency of IFN-␥ ϩ cells was not enhanced compared to that for similar cells treated with a peptide that was irrelevant to PVM infection (data not shown). Analysis of PVMspecific CD8 ϩ T cells within the draining mediastinal lymph nodes (MLN) in RP-002-treated mice on day 5 postinfection revealed significantly fewer PVM-specific CD8 ϩ T cells after stimulation with the PVM immunodominant peptide (Fig.…”
Section: Tnf-␣ and Ifn-␥ Are Essential For Initiating A Cytokine Stormentioning
confidence: 94%
“…Analysis of PVMspecific CD8 ϩ T cells within the draining mediastinal lymph nodes (MLN) in RP-002-treated mice on day 5 postinfection revealed significantly fewer PVM-specific CD8 ϩ T cells after stimulation with the PVM immunodominant peptide (Fig. 3D) (28) than for mice that received vehicle. Further, after PVM peptide stimulation, IFN-␥ ϩ CD8 ϩ T cells from RP-002 recipients had fewer singly TNF-␣-producing or dually TNF-␣/IL-2-producing cells (Fig.…”
Section: Tnf-␣ and Ifn-␥ Are Essential For Initiating A Cytokine Stormentioning
The cytokine storm is an intensified, dysregulated, tissue-injurious inflammatory response driven by cytokine and immune cell components. The cytokine storm during influenza virus infection, whereby the amplified innate immune response is primarily responsible for pulmonary damage, has been well characterized. Now we describe a novel event where virus-specific T cells induce a cytokine storm. The paramyxovirus pneumonia virus of mice (PVM) is a model of human respiratory syncytial virus (hRSV). Unexpectedly, when C57BL/6 mice were infected with PVM, the innate inflammatory response was undetectable until day 5 postinfection, at which time CD8؉ T cells infiltrated into the lung, initiating a cytokine storm by their production of gamma interferon (IFN-␥) and tumor necrosis factor alpha (TNF-␣). Administration of an immunomodulatory sphingosine-1-phosphate (S1P) receptor 1 (S1P1R) agonist significantly inhibited PVM-elicited cytokine storm by blunting the PVM-specific CD8 ؉ T cell response, resulting in diminished pulmonary disease and enhanced survival.
IMPORTANCEA dysregulated overly exuberant immune response, termed a "cytokine storm," accompanies virus-induced acute respiratory diseases (VARV), is primarily responsible for the accompanying high morbidity and mortality, and can be controlled therapeutically in influenza virus infection of mice and ferrets by administration of sphingosine-1-phosphate 1 receptor (S1P1R) agonists. Here, two novel findings are recorded. First, in contrast to influenza infection, where the cytokine storm is initiated early by the innate immune system, for pneumonia virus of mice (PVM), a model of RSV, the cytokine storm is initiated late in infection by the adaptive immune response: specifically, by virus-specific CD8 T cells via their release of IFN-␥ and TNF-␣. Blockading these cytokines with neutralizing antibodies blunts the cytokine storm and protects the host. Second, PVM infection is controlled by administration of an S1P1R agonist.
“…Of note, CD8 T cells in the same cultures did not respond to any of the peptides summarized in Table 1, except to peptide NP 333–347
( Supplementary Fig. S2), which included the GAPRNRELF sequence of the MHCI-restricted N 339–347 epitope 20 .Figure 2Identification of MHCII-restricted PVM epitopes recognized by CD4 T cells from PVM-infected mice. 8 week old C57BL/6 females were infected i.t.…”
Pneumonia virus of mice (PVM) infection has been widely used as a rodent model to study the closely related human respiratory syncytial virus (hRSV). While T cells are indispensable for viral clearance, they also contribute to immunopathology. To gain more insight into mechanistic details, novel tools are needed that allow to study virus-specific T cells in C57BL/6 mice as the majority of transgenic mice are only available on this background. While PVM-specific CD8 T cell epitopes were recently described, so far no PVM-specific CD4 T cell epitopes have been identified within the C57BL/6 strain. Therefore, we set out to map H2-IAb-restricted epitopes along the PVM proteome. By means of in silico prediction and subsequent functional validation, we were able to identify a MHCII-restricted CD4 T cell epitope, corresponding to amino acids 37–47 in the PVM matrix protein (M37–47). Using this newly identified MHCII-restricted M37–47 epitope and a previously described MHCI-restricted N339–347 epitope, we generated peptide-loaded MHCII and MHCI tetramers and characterized the dynamics of virus-specific CD4 and CD8 T cell responses in vivo. The findings of this study can provide a basis for detailed investigation of T cell-mediated immune responses to PVM in a variety of genetically modified C57BL/6 mice.
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