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RSV vaccine-enhanced disease is orchestrated by the combined actions of distinct CD4 T cell subsets.

Knudson CJ, Hartwig SM, Meyerholz DK, Varga SM - PLoS Pathog. (2015)

Bottom Line: We demonstrate for the first time that while CD4 T cells mediate all aspects of vaccine-enhanced disease, distinct CD4 T cell subsets orchestrate discrete and specific disease parameters.In contrast, the Th1-associated cytokine TNF-α was necessary to mediate airway obstruction and weight loss.Our data demonstrate that individual disease manifestations associated with FI-RSV vaccine-enhanced disease are mediated by distinct subsets of CD4 T cells.

View Article: PubMed Central - PubMed

Affiliation: Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, Iowa, United States of America.

ABSTRACT
There is no currently licensed vaccine for respiratory syncytial virus (RSV) despite being the leading cause of lower respiratory tract infections in children. Children previously immunized with a formalin-inactivated RSV (FI-RSV) vaccine exhibited enhanced respiratory disease following natural RSV infection. Subsequent studies in animal models have implicated roles for CD4 T cells, eosinophils and non-neutralizing antibodies in mediating enhanced respiratory disease. However, the underlying immunological mechanisms responsible for the enhanced respiratory disease and other disease manifestations associated with FI-RSV vaccine-enhanced disease remain unclear. We demonstrate for the first time that while CD4 T cells mediate all aspects of vaccine-enhanced disease, distinct CD4 T cell subsets orchestrate discrete and specific disease parameters. A Th2-biased immune response, but not eosinophils specifically, was required for airway hyperreactivity and mucus hypersecretion. In contrast, the Th1-associated cytokine TNF-α was necessary to mediate airway obstruction and weight loss. Our data demonstrate that individual disease manifestations associated with FI-RSV vaccine-enhanced disease are mediated by distinct subsets of CD4 T cells.

No MeSH data available.


Related in: MedlinePlus

Development of VED following RSV challenge of FI-RSV-immunized mice.(A) FI-mock- and FI-RSV-vaccinated mice were monitored daily for airway obstruction using a whole body plethysmograph. (B) Weight loss was assessed for immunized mice for 7 days following RSV challenge. (C) Total number of eosinophils (CD11cintSiglec F+), neutrophils (Ly6c+Ly6ghi), macrophages (CD11c+F4/80+), and T cell lymphocytes (CD90.2+) were quantified from the lungs of vaccinated mice via flow cytometry on day 4 and 6 post-RSV challenge. (D) Cytokine protein amounts in whole lung homogenates from immunized mice were determined on day 3 following RSV infection. Dotted lines indicate the limit of detection. (E) Total number of eosinophils from the lung parenchyma of FI-mock- and FI-RSV-immunized WT and dblGATA-1 mice were quantified on days 4 and 6 following RSV challenge. (F) Plaque assay on lungs from immunized WT and dblGATA-1 mice was performed on days 4 and 7 following RSV challenge. Data are represented as mean ± SEM from two independent experiments (n = 12 mice total for A, B, n = 8 for C-F). Groups were compared using Student's t-test for two groups or using one-way ANOVA for comparison of more than two groups, * p<0.05, ** p<0.01, *** p<0.001.
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ppat.1004757.g001: Development of VED following RSV challenge of FI-RSV-immunized mice.(A) FI-mock- and FI-RSV-vaccinated mice were monitored daily for airway obstruction using a whole body plethysmograph. (B) Weight loss was assessed for immunized mice for 7 days following RSV challenge. (C) Total number of eosinophils (CD11cintSiglec F+), neutrophils (Ly6c+Ly6ghi), macrophages (CD11c+F4/80+), and T cell lymphocytes (CD90.2+) were quantified from the lungs of vaccinated mice via flow cytometry on day 4 and 6 post-RSV challenge. (D) Cytokine protein amounts in whole lung homogenates from immunized mice were determined on day 3 following RSV infection. Dotted lines indicate the limit of detection. (E) Total number of eosinophils from the lung parenchyma of FI-mock- and FI-RSV-immunized WT and dblGATA-1 mice were quantified on days 4 and 6 following RSV challenge. (F) Plaque assay on lungs from immunized WT and dblGATA-1 mice was performed on days 4 and 7 following RSV challenge. Data are represented as mean ± SEM from two independent experiments (n = 12 mice total for A, B, n = 8 for C-F). Groups were compared using Student's t-test for two groups or using one-way ANOVA for comparison of more than two groups, * p<0.05, ** p<0.01, *** p<0.001.

Mentions: ERD was an important clinical manifestation of FI-RSV VED [5–7]. Whole body plethysmography has been previously utilized for the assessment of baseline respiratory patterns that correlate with pulmonary function following viral infections [15,16]. Therefore, we used unrestrained whole body plethysmography to evaluate pulmonary function daily following RSV challenge [17,18] of FI-RSV-immunized BALB/c mice. FI-RSV-primed mice exhibited increased airway obstruction, measured as enhanced pause (Penh, Fig. 1A), during the first five days following RSV challenge when compared to mock-primed controls. Mice vaccinated with FI-RSV also exhibited significantly (p<0.05) increased weight loss (Fig. 1B) compared to the mock-immunized control group between days 1–6 following RSV challenge. The numbers of eosinophils, macrophages and lymphocytes were significantly (p<0.01) increased in the lungs of FI-RSV-immunized mice on days 4 and 6 following RSV challenge (Fig. 1C). Consistent with the induction of pulmonary eosinophilia, FI-RSV-immunized animals exhibit significantly (p<0.001) increased protein amounts of the Th2-associated cytokines IL-4 and IL-13 as compared to mock-immunized controls at days 3 and 4 following RSV infection (Fig. 1D). In addition, there was a significant (p<0.001) increase in both lung IFN-γ and TNF-α protein amounts indicating that the CD4 T cell response consisted of a mixture of Th1 and Th2 cells. A significant difference in IL-17A production was not detected by either ELISA of lung homogenates or following CD4 T cell restimulation and therefore only the Th1- and Th2-associated immune responses were evaluated for the remainder of the study (S1 Fig.).


RSV vaccine-enhanced disease is orchestrated by the combined actions of distinct CD4 T cell subsets.

Knudson CJ, Hartwig SM, Meyerholz DK, Varga SM - PLoS Pathog. (2015)

Development of VED following RSV challenge of FI-RSV-immunized mice.(A) FI-mock- and FI-RSV-vaccinated mice were monitored daily for airway obstruction using a whole body plethysmograph. (B) Weight loss was assessed for immunized mice for 7 days following RSV challenge. (C) Total number of eosinophils (CD11cintSiglec F+), neutrophils (Ly6c+Ly6ghi), macrophages (CD11c+F4/80+), and T cell lymphocytes (CD90.2+) were quantified from the lungs of vaccinated mice via flow cytometry on day 4 and 6 post-RSV challenge. (D) Cytokine protein amounts in whole lung homogenates from immunized mice were determined on day 3 following RSV infection. Dotted lines indicate the limit of detection. (E) Total number of eosinophils from the lung parenchyma of FI-mock- and FI-RSV-immunized WT and dblGATA-1 mice were quantified on days 4 and 6 following RSV challenge. (F) Plaque assay on lungs from immunized WT and dblGATA-1 mice was performed on days 4 and 7 following RSV challenge. Data are represented as mean ± SEM from two independent experiments (n = 12 mice total for A, B, n = 8 for C-F). Groups were compared using Student's t-test for two groups or using one-way ANOVA for comparison of more than two groups, * p<0.05, ** p<0.01, *** p<0.001.
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ppat.1004757.g001: Development of VED following RSV challenge of FI-RSV-immunized mice.(A) FI-mock- and FI-RSV-vaccinated mice were monitored daily for airway obstruction using a whole body plethysmograph. (B) Weight loss was assessed for immunized mice for 7 days following RSV challenge. (C) Total number of eosinophils (CD11cintSiglec F+), neutrophils (Ly6c+Ly6ghi), macrophages (CD11c+F4/80+), and T cell lymphocytes (CD90.2+) were quantified from the lungs of vaccinated mice via flow cytometry on day 4 and 6 post-RSV challenge. (D) Cytokine protein amounts in whole lung homogenates from immunized mice were determined on day 3 following RSV infection. Dotted lines indicate the limit of detection. (E) Total number of eosinophils from the lung parenchyma of FI-mock- and FI-RSV-immunized WT and dblGATA-1 mice were quantified on days 4 and 6 following RSV challenge. (F) Plaque assay on lungs from immunized WT and dblGATA-1 mice was performed on days 4 and 7 following RSV challenge. Data are represented as mean ± SEM from two independent experiments (n = 12 mice total for A, B, n = 8 for C-F). Groups were compared using Student's t-test for two groups or using one-way ANOVA for comparison of more than two groups, * p<0.05, ** p<0.01, *** p<0.001.
Mentions: ERD was an important clinical manifestation of FI-RSV VED [5–7]. Whole body plethysmography has been previously utilized for the assessment of baseline respiratory patterns that correlate with pulmonary function following viral infections [15,16]. Therefore, we used unrestrained whole body plethysmography to evaluate pulmonary function daily following RSV challenge [17,18] of FI-RSV-immunized BALB/c mice. FI-RSV-primed mice exhibited increased airway obstruction, measured as enhanced pause (Penh, Fig. 1A), during the first five days following RSV challenge when compared to mock-primed controls. Mice vaccinated with FI-RSV also exhibited significantly (p<0.05) increased weight loss (Fig. 1B) compared to the mock-immunized control group between days 1–6 following RSV challenge. The numbers of eosinophils, macrophages and lymphocytes were significantly (p<0.01) increased in the lungs of FI-RSV-immunized mice on days 4 and 6 following RSV challenge (Fig. 1C). Consistent with the induction of pulmonary eosinophilia, FI-RSV-immunized animals exhibit significantly (p<0.001) increased protein amounts of the Th2-associated cytokines IL-4 and IL-13 as compared to mock-immunized controls at days 3 and 4 following RSV infection (Fig. 1D). In addition, there was a significant (p<0.001) increase in both lung IFN-γ and TNF-α protein amounts indicating that the CD4 T cell response consisted of a mixture of Th1 and Th2 cells. A significant difference in IL-17A production was not detected by either ELISA of lung homogenates or following CD4 T cell restimulation and therefore only the Th1- and Th2-associated immune responses were evaluated for the remainder of the study (S1 Fig.).

Bottom Line: We demonstrate for the first time that while CD4 T cells mediate all aspects of vaccine-enhanced disease, distinct CD4 T cell subsets orchestrate discrete and specific disease parameters.In contrast, the Th1-associated cytokine TNF-α was necessary to mediate airway obstruction and weight loss.Our data demonstrate that individual disease manifestations associated with FI-RSV vaccine-enhanced disease are mediated by distinct subsets of CD4 T cells.

View Article: PubMed Central - PubMed

Affiliation: Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, Iowa, United States of America.

ABSTRACT
There is no currently licensed vaccine for respiratory syncytial virus (RSV) despite being the leading cause of lower respiratory tract infections in children. Children previously immunized with a formalin-inactivated RSV (FI-RSV) vaccine exhibited enhanced respiratory disease following natural RSV infection. Subsequent studies in animal models have implicated roles for CD4 T cells, eosinophils and non-neutralizing antibodies in mediating enhanced respiratory disease. However, the underlying immunological mechanisms responsible for the enhanced respiratory disease and other disease manifestations associated with FI-RSV vaccine-enhanced disease remain unclear. We demonstrate for the first time that while CD4 T cells mediate all aspects of vaccine-enhanced disease, distinct CD4 T cell subsets orchestrate discrete and specific disease parameters. A Th2-biased immune response, but not eosinophils specifically, was required for airway hyperreactivity and mucus hypersecretion. In contrast, the Th1-associated cytokine TNF-α was necessary to mediate airway obstruction and weight loss. Our data demonstrate that individual disease manifestations associated with FI-RSV vaccine-enhanced disease are mediated by distinct subsets of CD4 T cells.

No MeSH data available.


Related in: MedlinePlus