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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

TNF-α contributes to airway obstruction and weight loss during FI-RSV VED.(A) WT and IFN-γ-deficient mice immunized with FI-RSV were challenged with RSV 3 weeks later and airway obstruction and weight loss were assessed daily. (B) BALB/c mice were immunized with FI-RSV and treated with either IgG or anti-TNF-α neutralization antibody prior to RSV challenge. Mice were assessed for airway obstruction and weight loss daily following infection. Data are represented as mean ± SEM of 2 independent experiments (n = 8 total mice). Groups were compared using one-way ANOVA, * p<0.05, ** p<0.01, *** p<0.001.
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ppat.1004757.g006: TNF-α contributes to airway obstruction and weight loss during FI-RSV VED.(A) WT and IFN-γ-deficient mice immunized with FI-RSV were challenged with RSV 3 weeks later and airway obstruction and weight loss were assessed daily. (B) BALB/c mice were immunized with FI-RSV and treated with either IgG or anti-TNF-α neutralization antibody prior to RSV challenge. Mice were assessed for airway obstruction and weight loss daily following infection. Data are represented as mean ± SEM of 2 independent experiments (n = 8 total mice). Groups were compared using one-way ANOVA, * p<0.05, ** p<0.01, *** p<0.001.

Mentions: We next investigated other immunological factors related to the CD4 T cell response that could mediate either the severe weight loss or airway obstruction associated with FI-RSV VED. Since there is a significant (p<0.01) increase the number of IFN-γ- and TNF-α-producing CD4 T cells in FI-RSV-immunized mice following RSV infection (Figs. 3C and D, and 4E), we assessed the roles of IFN-γ and TNF-α during FI-RSV VED. Despite a significant increase in IFN-γ protein amounts in the lung at day 3 post-infection of FI-RSV-vaccinated mice (Fig. 1D), FI-RSV-immunized IFN-γ-deficient mice displayed no alteration in either airway obstruction or weight loss (Fig. 6A) as compared to WT controls. In contrast, neutralization of TNF-α in FI-RSV-immunized mice significantly (p<0.05) reduced both the increase in airway obstruction and weight loss (Fig. 6B) following RSV infection.


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)

TNF-α contributes to airway obstruction and weight loss during FI-RSV VED.(A) WT and IFN-γ-deficient mice immunized with FI-RSV were challenged with RSV 3 weeks later and airway obstruction and weight loss were assessed daily. (B) BALB/c mice were immunized with FI-RSV and treated with either IgG or anti-TNF-α neutralization antibody prior to RSV challenge. Mice were assessed for airway obstruction and weight loss daily following infection. Data are represented as mean ± SEM of 2 independent experiments (n = 8 total mice). Groups were compared using one-way ANOVA, * p<0.05, ** p<0.01, *** p<0.001.
© Copyright Policy
Related In: Results  -  Collection

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

ppat.1004757.g006: TNF-α contributes to airway obstruction and weight loss during FI-RSV VED.(A) WT and IFN-γ-deficient mice immunized with FI-RSV were challenged with RSV 3 weeks later and airway obstruction and weight loss were assessed daily. (B) BALB/c mice were immunized with FI-RSV and treated with either IgG or anti-TNF-α neutralization antibody prior to RSV challenge. Mice were assessed for airway obstruction and weight loss daily following infection. Data are represented as mean ± SEM of 2 independent experiments (n = 8 total mice). Groups were compared using one-way ANOVA, * p<0.05, ** p<0.01, *** p<0.001.
Mentions: We next investigated other immunological factors related to the CD4 T cell response that could mediate either the severe weight loss or airway obstruction associated with FI-RSV VED. Since there is a significant (p<0.01) increase the number of IFN-γ- and TNF-α-producing CD4 T cells in FI-RSV-immunized mice following RSV infection (Figs. 3C and D, and 4E), we assessed the roles of IFN-γ and TNF-α during FI-RSV VED. Despite a significant increase in IFN-γ protein amounts in the lung at day 3 post-infection of FI-RSV-vaccinated mice (Fig. 1D), FI-RSV-immunized IFN-γ-deficient mice displayed no alteration in either airway obstruction or weight loss (Fig. 6A) as compared to WT controls. In contrast, neutralization of TNF-α in FI-RSV-immunized mice significantly (p<0.05) reduced both the increase in airway obstruction and weight loss (Fig. 6B) following RSV infection.

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