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IgE cross-linking impairs monocyte antiviral responses and inhibits influenza-driven TH1 differentiation  Regina K. Rowe, MD, PhD, David M. Pyle, MD,

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Presentation on theme: "IgE cross-linking impairs monocyte antiviral responses and inhibits influenza-driven TH1 differentiation  Regina K. Rowe, MD, PhD, David M. Pyle, MD,"— Presentation transcript:

1 IgE cross-linking impairs monocyte antiviral responses and inhibits influenza-driven TH1 differentiation  Regina K. Rowe, MD, PhD, David M. Pyle, MD, PhD, Andrew R. Tomlinson, MD, Tinghong Lv, BS, Zheng Hu, BS, Michelle A. Gill, MD, PhD  Journal of Allergy and Clinical Immunology  Volume 140, Issue 1, Pages e8 (July 2017) DOI: /j.jaci Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 IgE cross-linking inhibits virus-driven monocyte priming of TH1 cells. A, Naive CD4 T cells polarized with monocytes exposed to no virus (mock) or influenza A virus (Flu). B, Linear regression analysis was used to determine correlation between baseline monocyte FcεRI expression (x-axis) and TH1 priming capacity (% IFN-γ+ cells, y-axis) of influenza-exposed monocytes with P values and r2 values noted. N = 15. C and D, % IFN-γ+ T cells in monocyte-T-cell cocultures under IgE cross-linking conditions: (Fig 1, C) mean and (Fig 1, D) individual donor pairs. N = 15. E, Mean IFN-γ concentration in T-cell supernatants (N = 5). F, IgE cross-linking diminishes T-cell proliferation. Naive CD4 T cells labeled with VPD450 cellular dye before coculture. % divided defined as cells with lower VPD450 fluorescence compared with unstimulated T-cell controls, N = 3. Error bars represent the SEM. Pertinent P values are shown and were obtained with 2-way ANOVA analysis. G and H, Influenza A virus protein expression in monocytes at 6 and 24 hours postinfection by (Fig 1, G) flow cytometry of Flu-positive cells (NP/HA double positive) and (Fig 1, H) flow cytometry imaging at 6 hours postinfection (NP, green; HA, red). Shown is representative data from N = 3 experiments. HA, Influenza hemagglutinin; MESF, mean equivalent soluble fluorochrome; NP, influenza nucleoprotein. Error bars represent SEM, and P values represent results of 1-way ANOVA. All Material and Methods can be found in this article's Online Repository at Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 IgE cross-linking inhibits virus-induced monocyte maturation and monocyte-T- cell interactions. A-C, Monocytes treated with media alone (mock) or influenza A virus (Flu) ± IgE cross-linking or IgG control antibody and stained for various cell surface markers. Representative flow cytometry (Fig 2, A) imaging analysis and (Fig 2, B) histograms for CD86 and HLA-DR staining are shown for mock and Flu only (Fig 2, C). Mean cell surface marker expression by flow cytometry analysis of the mean equivalent soluble fluorochrome (MESF, expressed as ×103 units) value was determined under the various conditions, N = 3. D, Flow cytometry imaging analysis of monocyte-T-cell interactions. Cell clusters from monocyte-T-cell cocultures stained with anti-CD3 (green), anti–HLA-DR (yellow), and nuclei (red) were visualized, 60× magnification on the Amnis ImageStream flow cytometer (Amnis, Seattle, Wash). E, Quantitation of total monocyte-T-cell clusters was performed using the IDEAS Software (Amnis) (N = 3). Error bars represent SEM, and P values represent results of 1-way ANOVA. All Material and Methods can be found in this article's Online Repository at Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig E1 IgE cross-linking inhibits virus-driven monocyte T-cell priming and proliferation. Representative flow cytometry plots for Fig 1. Naive CD4 T cells polarized with monocytes exposed to no virus (mock) or influenza A virus (Flu) ± IgE cross-linking antibody (αIgE) or isotype IgG control. T cells were labeled with the cell proliferation dye, VPD450, before coculture. A, Zebra plots for IFN-γ expression versus VPD450 show decreased IFN-γ–positive cells in the presence of IgE cross-linking. B, Histograms show cell proliferation (measured by loss of VPD450 intensity, x-axis) of T cells stimulated with monocytes (black line) compared with unstimulated T cells in gray. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig E2 IgE cross-linking does not alter TH2 polarization. Naive CD4 T cells polarized with monocytes exposed to no virus (mock) or influenza A virus (Flu) ± IgE cross-linking antibody (αIgE) or isotype IgG control. Graphs shown are (A) mean percentages of IL-4+ IFN-γ− cells for the indicated conditions. N = 15 donor pairs. B, Mean IL-4 concentration in monocyte-T-cell coculture supernatants. N = 5 donor pairs; error bars represent SEM, and P values represent results of 2-way ANOVA. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig E3 IL-12 is not involved in TH1 polarization by influenza-exposed monocytes. IL-12 is a critical factor in TH1 development.E21 Neither blocking antibodies nor exogenous addition of IL-12 restored the IgE-mediated defect in TH1 differentiation. A, IL-12p70 production was measured in supernatants from monocytes treated ± IFN-γ for 18 hours followed by 24-hour incubation with media alone (mock), influenza A virus (Flu), or LPS. IL-12p70 was not detectable after influenza exposure, despite robust production under positive control conditions. Dashed line denotes the limit of detection. B, Monocyte-induced TH1 priming; mean % IFN-γ+ T cells in depicted conditions treated ± isotype control (black bars) or neutralizing IL-12 antibody (white bars). N = 3. C, % IFN-γ+ T cells ± rh IL-12. Representative data (of N = 3 experiments) is shown; error bars represent SEM and P values represent results of 1-way ANOVA. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig E4 IgE cross-linking suppresses TH1 priming independently of TNF-α, IL-6, and IL-10. Cytokine secretion from monocyte supernatants at 18 hours after influenza virus (Flu) ± IgE cross-linking was measured for (A) TNF-α, (B) IL-6, or (C) IL-10. These were secreted by monocytes upon IgE cross-linking,7 and in the presence of both IgE cross-linking and influenza. D-F, Neutralization of these cytokines did not impact influenza-induced TH1 priming or restore inhibition by IgE cross-linking. Mean percentages of IFN-γ+ T cells in monocyte-T-cell cocultures treated with isotype controls (black bars) or neutralizing antibodies (white bars) to (Fig E4, D) TNF-α, (Fig E4, E) IL-6, or (Fig E4, F) IL-10. Representative data from N = 3 experiments are shown; error bars represent SEM, and P values represent results of 1-way ANOVA. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Fig E5 Model of IgE-mediated inhibition of monocyte-driven TH1 priming. Upon monocyte influenza exposure, the normal antiviral response results in phenotypic maturation and upregulation of monocyte cell surface molecules, downstream antigen presentation, and strong TCR signal culminating in TH1 differentiation. In the setting of allergic stimulation, via IgE receptor (FcεRI) engagement, virus-induced monocyte maturation is inhibited, resulting in weak TCR signal and poor TH1 differentiation. Impaired TH1 production would have significant downstream effects, including decreased antiviral cytokine secretion (eg, IFN-γ), cytotoxic CD8+ T-cell development, and antigen-specific antibody production. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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