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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

Antibody response is unaltered in CD4 T cell depleted mice.BALB/c mice were immunized with either FI-mock or FI-RSV, 21 days later treated i.p. with IgG or α-CD4 antibody, and challenged with RSV 2 days following antibody treatment. Serum was collected from mice preimmunization, before infection with antibody treatment, and after infection on day 4 post-infection. Serum was assessed for levels of (A) total IgG, (B) IgG1, and (C) IgG2a starting at a 1:64 dilution of serum. Data are represented as mean ± SEM of two independent experiments (n = 8 mice total). Groups were compared using one-way ANOVA with Tukey-Kramer post-test analysis.
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ppat.1004757.g009: Antibody response is unaltered in CD4 T cell depleted mice.BALB/c mice were immunized with either FI-mock or FI-RSV, 21 days later treated i.p. with IgG or α-CD4 antibody, and challenged with RSV 2 days following antibody treatment. Serum was collected from mice preimmunization, before infection with antibody treatment, and after infection on day 4 post-infection. Serum was assessed for levels of (A) total IgG, (B) IgG1, and (C) IgG2a starting at a 1:64 dilution of serum. Data are represented as mean ± SEM of two independent experiments (n = 8 mice total). Groups were compared using one-way ANOVA with Tukey-Kramer post-test analysis.

Mentions: Previous work has indicated that the induction of non-neutralizing antibody responses and immune complex deposition may contribute to the development of FI-RSV ERD [13,14]. In contrast, our data indicate that both Th1- and Th2-associated cytokines play a critical role in mediating individual disease parameters associated with FI-RSV VED. CD4 T cell responses are significantly (p<0.01) increased in FI-RSV-immunized mice following RSV challenge and consist of a mixture of Th1 and Th2 cells (Fig. 3C and D). In addition, it has been shown that CD4 T cells are required for the histopathology associated with FI-RSV VED [20]. Therefore, we sought to evaluate whether or not CD4 T cells were solely responsible in mediating pulmonary dysfunction and weight loss associated with FI-RSV VED. Depletion of CD4 T cells prior to RSV challenge, led to a significant (p<0.05) amelioration of both airway obstruction and weight loss (Fig. 8A) in FI-RSV-immunized mice. Furthermore, the absence of FI-RSV epitope-specific CD4 T cells significantly (p<0.001) reduced the changes in airway resistance and compliance (Fig. 8B) observed in FI-RSV-immunized mice after RSV challenge. Importantly, the amelioration of disease in FI-RSV-immunized mice occurred despite similar antibody levels between IgG- and α-CD4-treated groups for total IgG (Fig. 9A), IgG1 (Fig. 9B), and IgG2a (Fig. 9C). Our results show that CD4 T cells are necessary to orchestrate an immune response that mediates all facets of 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)

Antibody response is unaltered in CD4 T cell depleted mice.BALB/c mice were immunized with either FI-mock or FI-RSV, 21 days later treated i.p. with IgG or α-CD4 antibody, and challenged with RSV 2 days following antibody treatment. Serum was collected from mice preimmunization, before infection with antibody treatment, and after infection on day 4 post-infection. Serum was assessed for levels of (A) total IgG, (B) IgG1, and (C) IgG2a starting at a 1:64 dilution of serum. Data are represented as mean ± SEM of two independent experiments (n = 8 mice total). Groups were compared using one-way ANOVA with Tukey-Kramer post-test analysis.
© Copyright Policy
Related In: Results  -  Collection

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

ppat.1004757.g009: Antibody response is unaltered in CD4 T cell depleted mice.BALB/c mice were immunized with either FI-mock or FI-RSV, 21 days later treated i.p. with IgG or α-CD4 antibody, and challenged with RSV 2 days following antibody treatment. Serum was collected from mice preimmunization, before infection with antibody treatment, and after infection on day 4 post-infection. Serum was assessed for levels of (A) total IgG, (B) IgG1, and (C) IgG2a starting at a 1:64 dilution of serum. Data are represented as mean ± SEM of two independent experiments (n = 8 mice total). Groups were compared using one-way ANOVA with Tukey-Kramer post-test analysis.
Mentions: Previous work has indicated that the induction of non-neutralizing antibody responses and immune complex deposition may contribute to the development of FI-RSV ERD [13,14]. In contrast, our data indicate that both Th1- and Th2-associated cytokines play a critical role in mediating individual disease parameters associated with FI-RSV VED. CD4 T cell responses are significantly (p<0.01) increased in FI-RSV-immunized mice following RSV challenge and consist of a mixture of Th1 and Th2 cells (Fig. 3C and D). In addition, it has been shown that CD4 T cells are required for the histopathology associated with FI-RSV VED [20]. Therefore, we sought to evaluate whether or not CD4 T cells were solely responsible in mediating pulmonary dysfunction and weight loss associated with FI-RSV VED. Depletion of CD4 T cells prior to RSV challenge, led to a significant (p<0.05) amelioration of both airway obstruction and weight loss (Fig. 8A) in FI-RSV-immunized mice. Furthermore, the absence of FI-RSV epitope-specific CD4 T cells significantly (p<0.001) reduced the changes in airway resistance and compliance (Fig. 8B) observed in FI-RSV-immunized mice after RSV challenge. Importantly, the amelioration of disease in FI-RSV-immunized mice occurred despite similar antibody levels between IgG- and α-CD4-treated groups for total IgG (Fig. 9A), IgG1 (Fig. 9B), and IgG2a (Fig. 9C). Our results show that CD4 T cells are necessary to orchestrate an immune response that mediates all facets of 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