Targeting Toll-like receptors on dendritic cells modifies the TH2 response to peanut allergens in vitro Pierre Pochard, PhD, Brian Vickery, MD, M. Cecilia.

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Targeting Toll-like receptors on dendritic cells modifies the TH2 response to peanut allergens in vitro Pierre Pochard, PhD, Brian Vickery, MD, M. Cecilia Berin, PhD, Alexander Grishin, PhD, Hugh A. Sampson, MD, Michael Caplan, MD, PhD, Kim Bottomly, PhD Journal of Allergy and Clinical Immunology Volume 126, Issue 1, Pages 92-97.e5 (July 2010) DOI: 10.1016/j.jaci.2010.04.003 Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 DC treatment with HKE alters T-cell immune responses to peanut. CD4+ T cells were cocultured (ratio 10:1) with CPE-pulsed BMDCs stimulated with CPE (50 μg/mL), HKE (1 bacterium per BMDC), or both for 72 hours. A, Concentrations in IL-4, IL-5, IL-13, and IFN-γ were determined. Concentrations represent means ± SEMs (n = 5). ∗P < .05. B, After 5 days, proliferation of CD3+ cells was analyzed by means of flow cytometry. One representative experiment of 5 is shown. CFSE, Carboxyfluorescein succinimidyl ester; CM, complete media. Journal of Allergy and Clinical Immunology 2010 126, 92-97.e5DOI: (10.1016/j.jaci.2010.04.003) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 HKE alters peanut response by triggering TLR signaling in DCs. Wild-type (WT) CD4+ T cells were cocultured (ratio 10:1) with CPE-pulsed BMDCs (WT vs MyD88/TRIF-KO) stimulated with CPE (50 μg/mL), HKE (1 bacterium per BMDC), or both for 72 hours. Concentrations of IL-4, IL-13, and IFN-γ were determined. Concentrations represent means ± SEMs (n = 5). After 5 days, proliferation of CD3+ cells was analyzed by means of flow cytometry. Percentages of proliferative cells are indicated by means ± SEMs (n = 5). Statistical differences are indicated as follows: ∗∗P < .01. CM, Complete media. Journal of Allergy and Clinical Immunology 2010 126, 92-97.e5DOI: (10.1016/j.jaci.2010.04.003) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 HKE has a long-lasting effect on peanut response. CD4+ T cells were cocultured (ratio 10:1) with BMDCs stimulated with CPE (50 μg/mL), HKE (1 bacterium per BMDC), or both. After 7 days, they were washed, counted, and cocultured with CPE-pulsed BMDCs for 72 hours. A, Supernatants were analyzed for the presence of IL-5, IL-13, IL-17, and IFN-γ. ∗P < .05, ∗∗P < .01. B, Proliferation of CD3+ cells was determined by means of flow cytometry. One representative experiment of 5 is shown. CFSE, Carboxyfluorescein succinimidyl ester; CM, complete media. Journal of Allergy and Clinical Immunology 2010 126, 92-97.e5DOI: (10.1016/j.jaci.2010.04.003) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 HKE changes peanut-induced cytokine production by BMDCs. BMDCs were stimulated either with CPE (50 μg/mL), HKE (ratio of 1 bacterium per BMDC), or both stimuli for 24 hours. Unstimulated BMDCs were used as controls. Supernatants were analyzed by means of ELISA for production of IL-10, IL-12, IL-6, and TNF-α. Concentrations represent means ± SEMs (n = 15). ∗P < .05, ∗∗P < .01. CM, Complete media. Journal of Allergy and Clinical Immunology 2010 126, 92-97.e5DOI: (10.1016/j.jaci.2010.04.003) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Adding TLR4 and TLR9 ligands to CPE stimulation synergizes IL-10 production, whereas only TLR9 leads to IL-12 synergy by BMDCs. BMDCs (wild-type [WT] vs TLR4-knockout [KO] or TLR9-KO) were either stimulated with CPE (50 μg/mL), ultrapure LPS (500 ng/mL), ultrapure CpG (500 ng/mL), or a combination of both stimuli for 24 hours. Supernatants were analyzed by means of ELISA for production of IL-10 and IL-12. Concentrations represent means ± SEMs (n = 4). ∗∗P ≤ .01. CM, Complete media. Journal of Allergy and Clinical Immunology 2010 126, 92-97.e5DOI: (10.1016/j.jaci.2010.04.003) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 E coli partially inhibits the peanut-induced immune response through IL-12 production. CD4+ T cells were cocultured (ratio 10:1) with CPE-pulsed BMDCs stimulated with CPE (50 μg/mL), HKE (1 bacterium per BMDC), or both for 72 hours. BMDCs were preincubated with either an anti–IL-12 antibody or isotype control at 20 μg/mL. The anti–IFN-γ antibody (20 μg/mL) was added with T cells. Antibody concentrations were maintained during the whole time of the coculture. Concentrations of IL-4, IL-5, and IL-13 were determined, as well as concentrations of IFN-γ and IL-10. Concentrations represent means ± SEMs. ∗∗P ≤ .01). After 5 days, proliferation of CD3+ cells was analyzed by means of flow cytometry. Four combined experiments involving at least 5 mice are shown. Journal of Allergy and Clinical Immunology 2010 126, 92-97.e5DOI: (10.1016/j.jaci.2010.04.003) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Stimulation of DCs with peanut allergens induces TLR-independent IL-17 secretion. CD4+ T cells were cocultured (ratio 10:1) with CPE-pulsed BMDCs stimulated with CPE (50 μg/mL), HKE (1 bacterium per BMDC), or both for 72 hours. A, Wild-type (WT) BMDCs and T cells were used. Concentrations of IL-17 were determined. Concentrations represent means ± SEMs (n = 5). ∗P < .05, ∗∗P ≤ .01). B, MyD88/TRIF double-knockout (KO) BMDCs and WT T cells were used. IL-17 concentration was measured. Concentrations represent means ± SEMs (n = 5). ∗P < .05, ∗∗P ≤ .01). CM, Complete media. Journal of Allergy and Clinical Immunology 2010 126, 92-97.e5DOI: (10.1016/j.jaci.2010.04.003) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

HKE alters peanut response by triggering TLR cell signaling HKE alters peanut response by triggering TLR cell signaling. Wild-type (WT) CD4+ T cells were cocultured (ratio 10:1) with CPE-pulsed BMDCs (WT vs MyD88/TRIF-knockout [KO]) stimulated with CPE (50 μg/mL), HKE (1 bacterium per BMDC), or both for 72 hours. After 5 days, proliferation of CD3+ cells was analyzed by means of flow cytometry. One representative experiment of 5 is shown. CFSE, Carboxyfluorescein succinimidyl ester; CM, complete media. Journal of Allergy and Clinical Immunology 2010 126, 92-97.e5DOI: (10.1016/j.jaci.2010.04.003) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

HKE enhances CPE-induced BMDC maturation HKE enhances CPE-induced BMDC maturation. Wild-type (WT) and MyD88-knockout BMDCs were stimulated with CPE (50 μg/mL) in the presence or absence of HKE (ratio of 1 bacterium per BMDC) or LPS (500 ng/mL) for 24 hours. BMDCs were analyzed for CD80, CD86, CD40, and IAb by means of flow cytometry. Solid histograms represent unstimulated BMDCs. One representative experiment of 5 is shown. Journal of Allergy and Clinical Immunology 2010 126, 92-97.e5DOI: (10.1016/j.jaci.2010.04.003) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Adding TLR4 or TLR9 ligands to CPE stimulation increases IL-6 and TNF-α production by BMDCs. Wild-type (WT), TLR4-knockout (KO), and TLR9-KO BMDCs were either stimulated with CPE (50 μg/mL), ultrapure LPS (500 ng/mL), ultrapure CpG (500 ng/mL), or a combination of both stimuli for 24 hours. Supernatants were analyzed by means of ELISA for production of TNF-α and IL-6. Concentrations represent means ± SEMs (n = 4). ∗∗P ≤ .01. CM, Complete media. Journal of Allergy and Clinical Immunology 2010 126, 92-97.e5DOI: (10.1016/j.jaci.2010.04.003) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

IL-10 is not responsible for HKE's effect on the CPE-induced immune response. CD4+ T cells (from IL-10–knockout mice) were cocultured (ratio 10:1) with CPE-pulsed BMDCs (from IL-10–knockout mice) stimulated with CPE (50 μg/mL), HKE (1 bacterium per BMDC), or both for 72 hours. A, Concentrations of IL-4, IL-5, IL-13, and IFN-γ were determined. Concentrations represent means ± SEMs (n = 5). ∗P < .05. B, After 5 days, proliferation of CD3+ cells was analyzed by means of flow cytometry. One representative experiment of 5 is shown. CFSE, Carboxyfluorescein succinimidyl ester; CM, complete media. Journal of Allergy and Clinical Immunology 2010 126, 92-97.e5DOI: (10.1016/j.jaci.2010.04.003) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions