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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 impaired in STAT6-deficient mice.(A) Cytokine protein amounts in the lungs of WT and STAT6 KO immunized mice were assessed on day 3 post-infection. Naïve controls were below the limit of detection for each cytokine. (B) RSV titers in the lungs of immunized WT and STAT6-deficient mice were determined via plaque assay on day 4 following RSV challenge. Number of (C) CD4 T cells and (D) eosinophils in the lungs of immunized mice were quantified on day 7 post-infection. (E) Number of Th1 and Th2 cytokine producing CD4 T cells in vaccinated WT and STAT6 KO mice on day 7 following RSV challenge were determined following PMA and ionomycin stimulation. Limit of detection for cytokine ELISA and plaque assay is denoted as a dotted line. Data are represented as mean ± SEM of two independent experiments (n = 8 mice total for A, B, n = 12 mice total for C-E). 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.g004: Th2-associated immune response is impaired in STAT6-deficient mice.(A) Cytokine protein amounts in the lungs of WT and STAT6 KO immunized mice were assessed on day 3 post-infection. Naïve controls were below the limit of detection for each cytokine. (B) RSV titers in the lungs of immunized WT and STAT6-deficient mice were determined via plaque assay on day 4 following RSV challenge. Number of (C) CD4 T cells and (D) eosinophils in the lungs of immunized mice were quantified on day 7 post-infection. (E) Number of Th1 and Th2 cytokine producing CD4 T cells in vaccinated WT and STAT6 KO mice on day 7 following RSV challenge were determined following PMA and ionomycin stimulation. Limit of detection for cytokine ELISA and plaque assay is denoted as a dotted line. Data are represented as mean ± SEM of two independent experiments (n = 8 mice total for A, B, n = 12 mice total for C-E). Groups were compared using one-way ANOVA at each time point, * p<0.05, ** p<0.01, *** p<0.001.

Mentions: We next questioned if Th2-associated responses were responsible for mediating all disease parameters associated with FI-RSV VED. The transcription factor STAT6 is crucial for the differentiation of naive CD4 T cells to Th2 cells and ultimately the induction of Th2-associated immune responses [23]. Therefore, we utilized STAT6-deficient mice to determine if Th2-biased immune responses were necessary to mediate all disease symptoms associated with FI-RSV VED. FI-RSV-immunized mice on day 3 post-infection exhibited a significant (p<0.01) reduction in both IL-4 and IL-13 protein amounts in the lung (Fig. 4A). STAT6 deficiency did not impact lung viral titers in either mock- or FI-RSV-immunized mice (Fig. 4B). The total number of CD4 T cells remained similar between WT and STAT6-deficient FI-RSV-immunized mice (Fig. 4C). However, on day 7 following RSV challenge FI-RSV-immunized STAT6-deficient mice exhibited a significant (p<0.001) reduction in the number of eosinophils in the lung (Fig. 4D). Moreover, the number of IL-5- and IL-13-producing CD4 T cells was significantly (p<0.01) reduced in FI-RSV-immunized STAT6-deficient mice at day 7 post-infection (Figs. 4E and S3). However, the number of IFN-γ-producing CD4 T cells remained similar in the lungs between FI-RSV-immunized STAT6-deficient and WT mice (Fig. 4E). These data demonstrate that the overall Th2-associated immune response in STAT6-deficient mice is severely diminished.


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 impaired in STAT6-deficient mice.(A) Cytokine protein amounts in the lungs of WT and STAT6 KO immunized mice were assessed on day 3 post-infection. Naïve controls were below the limit of detection for each cytokine. (B) RSV titers in the lungs of immunized WT and STAT6-deficient mice were determined via plaque assay on day 4 following RSV challenge. Number of (C) CD4 T cells and (D) eosinophils in the lungs of immunized mice were quantified on day 7 post-infection. (E) Number of Th1 and Th2 cytokine producing CD4 T cells in vaccinated WT and STAT6 KO mice on day 7 following RSV challenge were determined following PMA and ionomycin stimulation. Limit of detection for cytokine ELISA and plaque assay is denoted as a dotted line. Data are represented as mean ± SEM of two independent experiments (n = 8 mice total for A, B, n = 12 mice total for C-E). Groups were compared using one-way ANOVA at each time point, * p<0.05, ** p<0.01, *** p<0.001.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4358888&req=5

ppat.1004757.g004: Th2-associated immune response is impaired in STAT6-deficient mice.(A) Cytokine protein amounts in the lungs of WT and STAT6 KO immunized mice were assessed on day 3 post-infection. Naïve controls were below the limit of detection for each cytokine. (B) RSV titers in the lungs of immunized WT and STAT6-deficient mice were determined via plaque assay on day 4 following RSV challenge. Number of (C) CD4 T cells and (D) eosinophils in the lungs of immunized mice were quantified on day 7 post-infection. (E) Number of Th1 and Th2 cytokine producing CD4 T cells in vaccinated WT and STAT6 KO mice on day 7 following RSV challenge were determined following PMA and ionomycin stimulation. Limit of detection for cytokine ELISA and plaque assay is denoted as a dotted line. Data are represented as mean ± SEM of two independent experiments (n = 8 mice total for A, B, n = 12 mice total for C-E). Groups were compared using one-way ANOVA at each time point, * p<0.05, ** p<0.01, *** p<0.001.
Mentions: We next questioned if Th2-associated responses were responsible for mediating all disease parameters associated with FI-RSV VED. The transcription factor STAT6 is crucial for the differentiation of naive CD4 T cells to Th2 cells and ultimately the induction of Th2-associated immune responses [23]. Therefore, we utilized STAT6-deficient mice to determine if Th2-biased immune responses were necessary to mediate all disease symptoms associated with FI-RSV VED. FI-RSV-immunized mice on day 3 post-infection exhibited a significant (p<0.01) reduction in both IL-4 and IL-13 protein amounts in the lung (Fig. 4A). STAT6 deficiency did not impact lung viral titers in either mock- or FI-RSV-immunized mice (Fig. 4B). The total number of CD4 T cells remained similar between WT and STAT6-deficient FI-RSV-immunized mice (Fig. 4C). However, on day 7 following RSV challenge FI-RSV-immunized STAT6-deficient mice exhibited a significant (p<0.001) reduction in the number of eosinophils in the lung (Fig. 4D). Moreover, the number of IL-5- and IL-13-producing CD4 T cells was significantly (p<0.01) reduced in FI-RSV-immunized STAT6-deficient mice at day 7 post-infection (Figs. 4E and S3). However, the number of IFN-γ-producing CD4 T cells remained similar in the lungs between FI-RSV-immunized STAT6-deficient and WT mice (Fig. 4E). These data demonstrate that the overall Th2-associated immune response in STAT6-deficient mice is severely diminished.

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