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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

Th2-associated immune response is necessary for lung pathology and airway hyperreactivity.(A) Mock- or FI-RSV-immunized WT and STAT6-deficient mice were assessed daily for airway obstruction and weight loss following RSV challenge. (B) H&E and PAS staining on lung sections from immunized WT and STAT6 KO mice was performed on day 4 following RSV infection. Representative pictures for each group were taken at 200X magnification. (C) Stained lung sections were scored for degree of PVA, mucus, and total histopathology score. (D) Airway resistance and compliance in vaccinated WT or STAT6-deficient mice was evaluated on day 4 post-infection. Data are represented as mean ± SEM of two independent experiments (n = 12 mice total for A, n = 8 total mice for B-D). Groups were compared using one-way ANOVA at each time point, * p<0.05, ** p<0.01, *** p<0.001.
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ppat.1004757.g005: Th2-associated immune response is necessary for lung pathology and airway hyperreactivity.(A) Mock- or FI-RSV-immunized WT and STAT6-deficient mice were assessed daily for airway obstruction and weight loss following RSV challenge. (B) H&E and PAS staining on lung sections from immunized WT and STAT6 KO mice was performed on day 4 following RSV infection. Representative pictures for each group were taken at 200X magnification. (C) Stained lung sections were scored for degree of PVA, mucus, and total histopathology score. (D) Airway resistance and compliance in vaccinated WT or STAT6-deficient mice was evaluated on day 4 post-infection. Data are represented as mean ± SEM of two independent experiments (n = 12 mice total for A, n = 8 total mice for B-D). Groups were compared using one-way ANOVA at each time point, * p<0.05, ** p<0.01, *** p<0.001.

Mentions: We next sought to determine if the impaired Th2-associated immune response in STAT6-deficient mice would ameliorate disease associated with FI-RSV VED. The absence of STAT6-signaling did not significantly alter either the airway obstruction or weight loss (Fig. 5A) in FI-RSV-immunized mice following RSV challenge. In contrast, assessment of histopathology revealed multiple changes to the lung environment (Figs. 5B and S4). Specifically, FI-RSV-immunized STAT6-deficient mice exhibited significantly (p<0.001) reduced perivascular leukocytic aggregates as compared to the WT group (Fig. 5C). Mucus hypersecretion was also significantly (p<0.001) reduced in STAT6-deficient FI-RSV-immunized mice as compared to the WT control group. Assessment of AHR also revealed a significant (p<0.001) reduction in airway resistance and a significant (p<0.001) improvement in compliance (Fig. 5D) of FI-RSV-immunized STAT6-deficient mice as compared to WT control group. Overall, our results demonstrate that the Th2-associated immune response does not substantially contribute to either airway obstruction or weight loss associated with FI-RSV VED. However, the Th2-associated immune response is required to induce lower airway pathology, mucus hypersecretion and AHR.


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)

Th2-associated immune response is necessary for lung pathology and airway hyperreactivity.(A) Mock- or FI-RSV-immunized WT and STAT6-deficient mice were assessed daily for airway obstruction and weight loss following RSV challenge. (B) H&E and PAS staining on lung sections from immunized WT and STAT6 KO mice was performed on day 4 following RSV infection. Representative pictures for each group were taken at 200X magnification. (C) Stained lung sections were scored for degree of PVA, mucus, and total histopathology score. (D) Airway resistance and compliance in vaccinated WT or STAT6-deficient mice was evaluated on day 4 post-infection. Data are represented as mean ± SEM of two independent experiments (n = 12 mice total for A, n = 8 total mice for B-D). Groups were compared using one-way ANOVA at each time point, * p<0.05, ** p<0.01, *** p<0.001.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4358888&req=5

ppat.1004757.g005: Th2-associated immune response is necessary for lung pathology and airway hyperreactivity.(A) Mock- or FI-RSV-immunized WT and STAT6-deficient mice were assessed daily for airway obstruction and weight loss following RSV challenge. (B) H&E and PAS staining on lung sections from immunized WT and STAT6 KO mice was performed on day 4 following RSV infection. Representative pictures for each group were taken at 200X magnification. (C) Stained lung sections were scored for degree of PVA, mucus, and total histopathology score. (D) Airway resistance and compliance in vaccinated WT or STAT6-deficient mice was evaluated on day 4 post-infection. Data are represented as mean ± SEM of two independent experiments (n = 12 mice total for A, n = 8 total mice for B-D). Groups were compared using one-way ANOVA at each time point, * p<0.05, ** p<0.01, *** p<0.001.
Mentions: We next sought to determine if the impaired Th2-associated immune response in STAT6-deficient mice would ameliorate disease associated with FI-RSV VED. The absence of STAT6-signaling did not significantly alter either the airway obstruction or weight loss (Fig. 5A) in FI-RSV-immunized mice following RSV challenge. In contrast, assessment of histopathology revealed multiple changes to the lung environment (Figs. 5B and S4). Specifically, FI-RSV-immunized STAT6-deficient mice exhibited significantly (p<0.001) reduced perivascular leukocytic aggregates as compared to the WT group (Fig. 5C). Mucus hypersecretion was also significantly (p<0.001) reduced in STAT6-deficient FI-RSV-immunized mice as compared to the WT control group. Assessment of AHR also revealed a significant (p<0.001) reduction in airway resistance and a significant (p<0.001) improvement in compliance (Fig. 5D) of FI-RSV-immunized STAT6-deficient mice as compared to WT control group. Overall, our results demonstrate that the Th2-associated immune response does not substantially contribute to either airway obstruction or weight loss associated with FI-RSV VED. However, the Th2-associated immune response is required to induce lower airway pathology, mucus hypersecretion and AHR.

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