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Enhanced natural killer-cell and T-cell responses to influenza A virus during pregnancy
Alexander W. Kaya,1,
Julia Fukuyamab,
Natali Azizc,
Cornelia L. Dekkera,
Sally Mackeya,
Gary E. Swand,
Mark M. Davise,f,1,
Susan Holmesb, and
Catherine A. Blishf,g,1
Author Affiliations
Contributed by Mark M. Davis, August 27, 2014 (sent for review July 20, 2014)
Abstract
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Significance
Pregnant women are subject to increased morbidity and mortality after influenza-virus infection. Pregnancy-induced suppression of the cellular immune system to promote fetal tolerance has been suggested as a potential mechanism. Here, we report that, whereas pregnant women indeed have decreased natural killer (NK)- and T-cell functional responses after nonspecific stimulation with phorbol 12-myristate 13-acetate and ionomycin, they have significantly increased NK- and T-cell responses to influenza virus compared with nonpregnant women. Intriguingly, these differences were present prior to influenza vaccination and were further enhanced after vaccination. Collectively, our data suggest a model in which an enhanced inflammatory response to influenza during pregnancy results in additional pathology in pregnant women, providing a potential explanation for their disproportionate morbidity and mortality.
Abstract
Pregnant women experience increased morbidity and mortality after influenza infection, for reasons that are not understood. Although some data suggest that natural killer (NK)- and T-cell responses are suppressed during pregnancy, influenza-specific responses have not been previously evaluated. Thus, we analyzed the responses of women that were pregnant (n = 21) versus those that were not (n = 29) immediately before inactivated influenza vaccination (IIV), 7 d after vaccination, and 6 wk postpartum. Expression of CD107a (a marker of cytolysis) and production of IFN-γ and macrophage inflammatory protein (MIP) 1β were assessed by flow cytometry. Pregnant women had a significantly increased percentage of NK cells producing a MIP-1β response to pH1N1 virus compared with nonpregnant women pre-IIV [median, 6.66 vs. 0.90% (P = 0.0149)] and 7 d post-IIV [median, 11.23 vs. 2.81% (P = 0.004)], indicating a heightened chemokine response in pregnant women that was further enhanced by the vaccination. Pregnant women also exhibited significantly increased T-cell production of MIP-1β and polyfunctionality in NK and T cells to pH1N1 virus pre- and post-IIV. NK- and T-cell polyfunctionality was also enhanced in pregnant women in response to the H3N2 viral strain. In contrast, pregnant women had significantly reduced NK- and T-cell responses to phorbol 12-myristate 13-acetate and ionomycin. This type of stimulation led to the conclusion that NK- and T-cell responses during pregnancy are suppressed, but clearly this conclusion is not correct relative to the more biologically relevant assays described here. Robust cellular immune responses to influenza during pregnancy could drive pulmonary inflammation, explaining increased morbidity and mortality.
http://www.pnas.org/content/early/2014/09/16/1416569111.abstract
Alexander W. Kaya,1,
Julia Fukuyamab,
Natali Azizc,
Cornelia L. Dekkera,
Sally Mackeya,
Gary E. Swand,
Mark M. Davise,f,1,
Susan Holmesb, and
Catherine A. Blishf,g,1
Author Affiliations
Contributed by Mark M. Davis, August 27, 2014 (sent for review July 20, 2014)
Abstract
Authors & Info
SI
Metrics
Related Content
PDF + SI
Significance
Pregnant women are subject to increased morbidity and mortality after influenza-virus infection. Pregnancy-induced suppression of the cellular immune system to promote fetal tolerance has been suggested as a potential mechanism. Here, we report that, whereas pregnant women indeed have decreased natural killer (NK)- and T-cell functional responses after nonspecific stimulation with phorbol 12-myristate 13-acetate and ionomycin, they have significantly increased NK- and T-cell responses to influenza virus compared with nonpregnant women. Intriguingly, these differences were present prior to influenza vaccination and were further enhanced after vaccination. Collectively, our data suggest a model in which an enhanced inflammatory response to influenza during pregnancy results in additional pathology in pregnant women, providing a potential explanation for their disproportionate morbidity and mortality.
Abstract
Pregnant women experience increased morbidity and mortality after influenza infection, for reasons that are not understood. Although some data suggest that natural killer (NK)- and T-cell responses are suppressed during pregnancy, influenza-specific responses have not been previously evaluated. Thus, we analyzed the responses of women that were pregnant (n = 21) versus those that were not (n = 29) immediately before inactivated influenza vaccination (IIV), 7 d after vaccination, and 6 wk postpartum. Expression of CD107a (a marker of cytolysis) and production of IFN-γ and macrophage inflammatory protein (MIP) 1β were assessed by flow cytometry. Pregnant women had a significantly increased percentage of NK cells producing a MIP-1β response to pH1N1 virus compared with nonpregnant women pre-IIV [median, 6.66 vs. 0.90% (P = 0.0149)] and 7 d post-IIV [median, 11.23 vs. 2.81% (P = 0.004)], indicating a heightened chemokine response in pregnant women that was further enhanced by the vaccination. Pregnant women also exhibited significantly increased T-cell production of MIP-1β and polyfunctionality in NK and T cells to pH1N1 virus pre- and post-IIV. NK- and T-cell polyfunctionality was also enhanced in pregnant women in response to the H3N2 viral strain. In contrast, pregnant women had significantly reduced NK- and T-cell responses to phorbol 12-myristate 13-acetate and ionomycin. This type of stimulation led to the conclusion that NK- and T-cell responses during pregnancy are suppressed, but clearly this conclusion is not correct relative to the more biologically relevant assays described here. Robust cellular immune responses to influenza during pregnancy could drive pulmonary inflammation, explaining increased morbidity and mortality.
http://www.pnas.org/content/early/2014/09/16/1416569111.abstract