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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

Absence of eosinophils does not affect T cell responses.Total number of (A) CD4 and (B) CD8 T cells in the lung of vaccinated WT and eosinophil-deficient mice was enumerated on days 4 and 6 following RSV infection. Number of IL-10, IFN-γ, IL-5, and IL-13 producing CD4 T cells in the lungs of immunized WT and dblGATA-1 mice was determined on days (C) 4 and (D) 6 post-infection. Data are represented as mean ± SEM of two independent experiments (n = 7 mice total for FI-mock, n = 8 mice for FI-RSV). Groups were compared using one-way ANOVA, ** p<0.01, *** p<0.001.
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ppat.1004757.g003: Absence of eosinophils does not affect T cell responses.Total number of (A) CD4 and (B) CD8 T cells in the lung of vaccinated WT and eosinophil-deficient mice was enumerated on days 4 and 6 following RSV infection. Number of IL-10, IFN-γ, IL-5, and IL-13 producing CD4 T cells in the lungs of immunized WT and dblGATA-1 mice was determined on days (C) 4 and (D) 6 post-infection. Data are represented as mean ± SEM of two independent experiments (n = 7 mice total for FI-mock, n = 8 mice for FI-RSV). Groups were compared using one-way ANOVA, ** p<0.01, *** p<0.001.

Mentions: Previous work has shown that antibody-mediated depletion of CD4 T cells in FI-RSV vaccinated mice prior to RSV challenge ameliorates pulmonary histopathology suggesting a vital role of CD4 T cells in mediating pulmonary inflammation following RSV challenge [20]. We observed a significant (p<0.001) increase in the number of CD4 T cells in the lung on days 4 and 6 post-RSV challenge (Fig. 3A) of FI-RSV-immunized mice compared to the mock-immunized control group. Importantly, the number of CD4 T cells in the lung was not significantly altered in the absence of eosinophils (Fig. 3A). Consistent with the notion that inactivated vaccines are poor at eliciting CD8 T cell responses, we have previously reported that FI-RSV immunization fails to induce an RSV-specific CD8 T cell memory response [21,22]. In agreement with our previous results, we observed no significant increase in the CD8 T cell response of FI-RSV-vaccinated mice (Fig. 3B). In contrast, we observed a robust secondary CD4 T cell response. We next evaluated subsets of CD4 T cells by intracellular cytokine staining following PMA and ionomycin restimulation (S2 Fig.). By day 6 following RSV challenge there was a significant (p<0.01) increase in the number of CD4 T cells that produced either IFN-γ or IL-13 following restimulation in FI-RSV-immunized mice as compared to mock control groups regardless of whether or not eosinophils were present (Fig. 3C and D). Our results indicate that independent of the presence of eosinophils, FI-RSV immunization primes both a Th1 and Th2 memory CD4 T cell response that may promote disease associated with FI-RSV VED.


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)

Absence of eosinophils does not affect T cell responses.Total number of (A) CD4 and (B) CD8 T cells in the lung of vaccinated WT and eosinophil-deficient mice was enumerated on days 4 and 6 following RSV infection. Number of IL-10, IFN-γ, IL-5, and IL-13 producing CD4 T cells in the lungs of immunized WT and dblGATA-1 mice was determined on days (C) 4 and (D) 6 post-infection. Data are represented as mean ± SEM of two independent experiments (n = 7 mice total for FI-mock, n = 8 mice for FI-RSV). Groups were compared using one-way ANOVA, ** p<0.01, *** p<0.001.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4358888&req=5

ppat.1004757.g003: Absence of eosinophils does not affect T cell responses.Total number of (A) CD4 and (B) CD8 T cells in the lung of vaccinated WT and eosinophil-deficient mice was enumerated on days 4 and 6 following RSV infection. Number of IL-10, IFN-γ, IL-5, and IL-13 producing CD4 T cells in the lungs of immunized WT and dblGATA-1 mice was determined on days (C) 4 and (D) 6 post-infection. Data are represented as mean ± SEM of two independent experiments (n = 7 mice total for FI-mock, n = 8 mice for FI-RSV). Groups were compared using one-way ANOVA, ** p<0.01, *** p<0.001.
Mentions: Previous work has shown that antibody-mediated depletion of CD4 T cells in FI-RSV vaccinated mice prior to RSV challenge ameliorates pulmonary histopathology suggesting a vital role of CD4 T cells in mediating pulmonary inflammation following RSV challenge [20]. We observed a significant (p<0.001) increase in the number of CD4 T cells in the lung on days 4 and 6 post-RSV challenge (Fig. 3A) of FI-RSV-immunized mice compared to the mock-immunized control group. Importantly, the number of CD4 T cells in the lung was not significantly altered in the absence of eosinophils (Fig. 3A). Consistent with the notion that inactivated vaccines are poor at eliciting CD8 T cell responses, we have previously reported that FI-RSV immunization fails to induce an RSV-specific CD8 T cell memory response [21,22]. In agreement with our previous results, we observed no significant increase in the CD8 T cell response of FI-RSV-vaccinated mice (Fig. 3B). In contrast, we observed a robust secondary CD4 T cell response. We next evaluated subsets of CD4 T cells by intracellular cytokine staining following PMA and ionomycin restimulation (S2 Fig.). By day 6 following RSV challenge there was a significant (p<0.01) increase in the number of CD4 T cells that produced either IFN-γ or IL-13 following restimulation in FI-RSV-immunized mice as compared to mock control groups regardless of whether or not eosinophils were present (Fig. 3C and D). Our results indicate that independent of the presence of eosinophils, FI-RSV immunization primes both a Th1 and Th2 memory CD4 T cell response that may promote disease associated with FI-RSV VED.

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