Notch signaling in T cells is essential for allergic airway inflammation, but expression of the Notch ligands Jagged 1 and Jagged 2 on dendritic cells.

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Notch signaling in T cells is essential for allergic airway inflammation, but expression of the Notch ligands Jagged 1 and Jagged 2 on dendritic cells is dispensable Irma Tindemans, MSc, Melanie Lukkes, BSc, Marjolein J.W. de Bruijn, BSc, Bobby W.S. Li, MSc, Menno van Nimwegen, BSc, Derk Amsen, PhD, Alex KleinJan, PhD, Rudi W. Hendriks, PhD Journal of Allergy and Clinical Immunology Volume 140, Issue 4, Pages 1079-1089 (October 2017) DOI: 10.1016/j.jaci.2016.11.046 Copyright © 2017 Terms and Conditions

Journal of Allergy and Clinical Immunology 2017 140, 1079-1089DOI: (10 Journal of Allergy and Clinical Immunology 2017 140, 1079-1089DOI: (10.1016/j.jaci.2016.11.046) Copyright © 2017 Terms and Conditions

Fig 1 Jagged 1 is upregulated on BMDCs on HDM exposure, and CD11c-Cre is effective in GM-CSF BMDCs. A, Flow cytometric gating strategy for BMDC subsets from C57BL/6 mice. Live cells were analyzed for CD11c and MHC class II and gated as indicated (top). mRNA expression of the indicated Notch ligands quantified by using quantitative real-time PCR (qRT-PCR) in GM-MoDCs, GM-DCs, and GM-macrophages and stimulated overnight in the presence or absence of HDM or LPS, as indicated (bottom). B, Quantification of relative Jagged 1 and Jagged 2 expression by using qRT-PCR in BMDC subsets that were fluorescence-activated cell sorted from Jg1Jg2ΔCD11c/ΔCD11c mice compared with WT C57BL/6 mice, which were set to 100%. Data are shown as means + SEMs of 4 mice per group in 1 experiment, except for HDM-stimulated GM-DCs (n = 2 in Fig 1, A, and n = 1 in Fig 1, B). *P < .05, Mann-Whitney U test. Journal of Allergy and Clinical Immunology 2017 140, 1079-1089DOI: (10.1016/j.jaci.2016.11.046) Copyright © 2017 Terms and Conditions

Fig 2 Jagged 1 and Jagged 2 are crucial during the sensitization phase when using GM-CSF BMDCs to induce AAI. A, Sensitization and challenge scheme of HDM-driven AAI in mice using cultured total BMDCs. B, Numbers of macrophages (FSChighSSChighAutofluorescent+CD11c+Siglec-F+), eosinophils (FSCintSSChighSiglec-F+), neutrophils (Ly-6G+), B cells (CD19+), T cells (CD3+), and DCs (CD11c+MHC class IIhi) in BAL fluid in mice treated with either PBS-pulsed or HDM-pulsed BMDCs from Jg1Jg2ΔCD11c/ΔCD11c or Jg1Jg2+/+ mice. FSC, Forward scatter; SSC, side scatter. C, Numbers of IL-4+, IL-5+, IL-13+, IFN-γ+, and IL-17A+ CD3+CD4+ T cells in BAL fluid in mice treated with either PBS-pulsed or HDM-pulsed BMDCs. D, Flow cytometric profile of Gata-3/Rorγt expression in CD3+CD4+ T cells in mice treated with HDM-pulsed BMDCs from Jg1Jg2ΔCD11c/ΔCD11c or Jg1Jg2+/+ mice. E, Total numbers of Gata-3+, Rorγt+, and Foxp3+CD25+ CD3+CD4+ T cells in MedLNs from mice treated with PBS- or HDM-pulsed BMDCs from Jg1Jg2ΔCD11c/ΔCD11c or Jg1Jg2+/+ mice, as indicated. Data are shown as means + SEMs of 4 (PBS) or 6 (HDM) mice per group in 1 experiment. *P < .05 and **P < .01, Mann-Whitney U test. Journal of Allergy and Clinical Immunology 2017 140, 1079-1089DOI: (10.1016/j.jaci.2016.11.046) Copyright © 2017 Terms and Conditions

Fig 3 Jagged 1 is upregulated on migratory CD11b+ cDCs on HDM exposure, and CD11c-Cre is effective in in vivo DCs. A, Gating strategy of ex vivo–sorted DC subsets from C57BL/6 mice intranasally treated with 50 μg of HDM or PBS (top). mRNA expression of the indicated Notch ligands, as determined by using qRT-PCR, in DAPI−MHC class IIhiCD11b+CD103−CD64− (migratory) DCs from MedLNs after 72 hours of in vivo stimulation (bottom). Six mice were pooled per sample. Data are shown as means + SEMs of 3 samples per group in 1 experiment. B, EYFP expression in CD11c+MHC class IIhi DCs in the indicated tissues from WT×ROSAEYFP and CD11c-Cre×ROSAEYFP mice after 72 hours of in vivo stimulation with 50 μg of HDM or PBS. Data are shown as histogram overlays of EYFP expression in the indicated mice. Samples were concatenated, and data are shown as means + SDs of 4 mice (CD11c-Cre×ROSAEYFP) or 2 to 3 mice (WT×ROSAEYFP) per group in 1 experiment. Journal of Allergy and Clinical Immunology 2017 140, 1079-1089DOI: (10.1016/j.jaci.2016.11.046) Copyright © 2017 Terms and Conditions

Fig 4 Jagged 1 and Jagged 2 expression on DCs is dispensable for the development of AAI in vivo. A, Scheme of HDM-mediated AAI induction in mice. B, Total numbers of indicated cell populations in BAL fluid from PBS- or HDM-treated Jg1Jg2ΔCD11c/ΔCD11c or Jg1Jg2+/+ mice. C and D, Intracellular flow cytometric analysis of cytokine production by CD3+CD4+ T cells in BAL fluid from the indicated mice (Fig 4, C) and quantification of total numbers of cytokine-positive CD3+CD4+ T cells in BAL fluid (Fig 4, D). E, Quantification of IL-5 production in vitro by MedLN cells restimulated with 15 μg/mL HDM for 7 days, as quantified by means of ELISA. F, Numbers of Gata-3+, Rorγt+, and Foxp3+CD25+ CD3+CD4+ T cells in BAL fluid from PBS- or HDM-treated Jg1Jg2ΔCD11c/ΔCD11c or Jg1Jg2+/+ mice. G, Total IgE levels and levels of HDM-specific IgE and IgG1 in serum of indicated mice. H, Cell counts of eosinophils and IL-5+CD3+CD4+ T cells in BAL fluid from PBS- or HDM-treated Jg1ΔCD11c and Jg2ΔCD11c mice with WT littermates. Data are shown as means + SEMs of 6 to 7 mice per group and are representative of 3 independent experiments. *P < .05 and **P < .01, Mann-Whitney U test. Journal of Allergy and Clinical Immunology 2017 140, 1079-1089DOI: (10.1016/j.jaci.2016.11.046) Copyright © 2017 Terms and Conditions

Fig 5 Notch signaling in CD4+ T cells is crucial for AAI induction. A, Scheme of HDM-mediated AAI induction in RBPJκΔCD4/ΔCD4 and RBPJκ+/+ mice. B, Total numbers of the indicated cell populations in BAL fluid from PBS- or HDM-treated mice. C-E, Intracellular flow cytometric analysis of cytokine production by CD3+CD4+ T cells in BAL fluid from the indicated mice (Fig 5, C), quantification of total numbers of cytokine-positive CD3+CD4+ T cells in BAL fluid (Fig 5, D), and distribution of TH1, TH2, and TH17 cells (Fig 5, E), as signified by the key cytokines IL-5, IFN-γ, and IL-17A in BAL fluid of indicated mice. F, Flow cytometric profile of transcription factor expression in CD3+CD4+ T cells in mice treated with HDM. G, Quantification of Gata-3+, Rorγt+, and Foxp3+ CD4+ T cells and CD49b+ CD4+ natural killer T cells in BAL fluid. H, Total IgE levels in serum, as determined by means of ELISA. I, Airway resistance, as measured directly after administration of increasing doses of methacholine by using flexiVent in indicated mouse groups. Data are shown as means + SEMs of 4 to 6 mice per group (Fig 5, B-I) and are representative of 6 independent experiments (Fig 5, B-H). *P < .05 and **P < .01, Mann-Whitney U test. Journal of Allergy and Clinical Immunology 2017 140, 1079-1089DOI: (10.1016/j.jaci.2016.11.046) Copyright © 2017 Terms and Conditions