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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

Eosinophils are not required to mediate FI-RSV VED.(A) WT and dblGATA-1 mice vaccinated with FI-RSV were assessed daily for airway obstruction and weight loss following RSV challenge. (B) Hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) staining were performed on lungs from immunized mice 4 days following RSV challenge. Numbers to the left indicate power of magnification. (C) Perivascular aggregates of leukocytes (PVA), mucus, and total histology scores from immunized WT and dblGATA-1 mice were determined on day 4 following infection. (D) Airway resistance and compliance were determined in vaccinated mice 4 days post-infection. Data is represented as percentage change following methacholine administration over baseline values obtained following saline treatment. Data are represented as mean ± SEM of two independent experiments (n = 12 mice total for A, n = 8 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.g002: Eosinophils are not required to mediate FI-RSV VED.(A) WT and dblGATA-1 mice vaccinated with FI-RSV were assessed daily for airway obstruction and weight loss following RSV challenge. (B) Hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) staining were performed on lungs from immunized mice 4 days following RSV challenge. Numbers to the left indicate power of magnification. (C) Perivascular aggregates of leukocytes (PVA), mucus, and total histology scores from immunized WT and dblGATA-1 mice were determined on day 4 following infection. (D) Airway resistance and compliance were determined in vaccinated mice 4 days post-infection. Data is represented as percentage change following methacholine administration over baseline values obtained following saline treatment. Data are represented as mean ± SEM of two independent experiments (n = 12 mice total for A, n = 8 for B-D). Groups were compared using one-way ANOVA at each time point, * p<0.05, ** p<0.01, *** p<0.001.

Mentions: Airway obstruction (Fig. 2A) was not significantly altered between eosinophil-deficient and wild-type (WT) FI-RSV-immunized mice following RSV challenge. Weight loss through day 6 following RSV challenge was also largely unaffected in FI-RSV-vaccinated dblGATA-1 mice. On day 7 post-infection, weight recovery was slightly delayed in FI-RSV-immunized eosinophil-deficient mice. We also compared the histopathology between vaccinated WT and eosinophil-deficient mice on day 4 following RSV challenge. Following RSV infection of mock-immunized mice, an increase in leukocytic aggregates around airways and mucus hypersecretion was noted as compared to naive mice (Fig. 2B and C). However, neither histopathology nor mucus levels were significantly altered in the absence of eosinophils in FI-RSV-immunized mice.


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)

Eosinophils are not required to mediate FI-RSV VED.(A) WT and dblGATA-1 mice vaccinated with FI-RSV were assessed daily for airway obstruction and weight loss following RSV challenge. (B) Hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) staining were performed on lungs from immunized mice 4 days following RSV challenge. Numbers to the left indicate power of magnification. (C) Perivascular aggregates of leukocytes (PVA), mucus, and total histology scores from immunized WT and dblGATA-1 mice were determined on day 4 following infection. (D) Airway resistance and compliance were determined in vaccinated mice 4 days post-infection. Data is represented as percentage change following methacholine administration over baseline values obtained following saline treatment. Data are represented as mean ± SEM of two independent experiments (n = 12 mice total for A, n = 8 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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getmorefigures.php?uid=PMC4358888&req=5

ppat.1004757.g002: Eosinophils are not required to mediate FI-RSV VED.(A) WT and dblGATA-1 mice vaccinated with FI-RSV were assessed daily for airway obstruction and weight loss following RSV challenge. (B) Hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) staining were performed on lungs from immunized mice 4 days following RSV challenge. Numbers to the left indicate power of magnification. (C) Perivascular aggregates of leukocytes (PVA), mucus, and total histology scores from immunized WT and dblGATA-1 mice were determined on day 4 following infection. (D) Airway resistance and compliance were determined in vaccinated mice 4 days post-infection. Data is represented as percentage change following methacholine administration over baseline values obtained following saline treatment. Data are represented as mean ± SEM of two independent experiments (n = 12 mice total for A, n = 8 for B-D). Groups were compared using one-way ANOVA at each time point, * p<0.05, ** p<0.01, *** p<0.001.
Mentions: Airway obstruction (Fig. 2A) was not significantly altered between eosinophil-deficient and wild-type (WT) FI-RSV-immunized mice following RSV challenge. Weight loss through day 6 following RSV challenge was also largely unaffected in FI-RSV-vaccinated dblGATA-1 mice. On day 7 post-infection, weight recovery was slightly delayed in FI-RSV-immunized eosinophil-deficient mice. We also compared the histopathology between vaccinated WT and eosinophil-deficient mice on day 4 following RSV challenge. Following RSV infection of mock-immunized mice, an increase in leukocytic aggregates around airways and mucus hypersecretion was noted as compared to naive mice (Fig. 2B and C). However, neither histopathology nor mucus levels were significantly altered in the absence of eosinophils in FI-RSV-immunized mice.

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