Targeting allergen to FcγRI reveals a novel TH2 regulatory pathway linked to thymic stromal lymphopoietin receptor Kathryn E. Hulse, PhD, Amanda J. Reefer,

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Targeting allergen to FcγRI reveals a novel TH2 regulatory pathway linked to thymic stromal lymphopoietin receptor Kathryn E. Hulse, PhD, Amanda J. Reefer, MS, Victor H. Engelhard, PhD, James T. Patrie, MS, Steven F. Ziegler, PhD, Martin D. Chapman, PhD, Judith A. Woodfolk, MBChB, PhD Journal of Allergy and Clinical Immunology Volume 125, Issue 1, Pages 247-256.e8 (January 2010) DOI: 10.1016/j.jaci.2009.10.027 Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 The TH2-promoting effect of TSLP is weak in atopic subjects. CD4+ T cells were cocultured with moDCs primed for 48 hours with TSLP. A, Cells were stained for intracellular cytokines (day 10) and analyzed by means of flow cytometry, gating on CD4+ T cells. Relative change for each T-cell type compared with nonstimulated cells is expressed as NI (n = 5 subjects per group). Error bars represent 95% CIs. B, Representative dot plots showing nonstimulated (NS) and TSLP-stimulated CD4+ T cells stained for IL-4 and IFN-γ. Percentages of cells in each quadrant are shown. C, Secreted cytokines in nonstimulated (NS) and TSLP-stimulated cultures (n = 5 subjects per group). Bars represent means ± SEMs. ∗Significant versus control group. Journal of Allergy and Clinical Immunology 2010 125, 247-256.e8DOI: (10.1016/j.jaci.2009.10.027) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Dendritic cells coprimed with H22–Fel d 1 and TSLP provide a potent TH2 stimulus in atopic subjects. CD4+ T cells were cocultured with moDCs that had been primed for 48 hours with Fel d 1 (Fel), H22–Fel d 1 (H-Fel), TSLP, or H22–Fel d 1 plus TSLP. Cytokine-positive T cells were analyzed on day 10. A, Summary data showing the percentage of each T-cell type induced by different stimuli (n = 5 subjects per group). Values are geometric means. Black and gray asterisks denote significant differences for IL-10+ and IL-4+ cell types, respectively, after adjusting for multiple comparisons. B, Relative change in each T-cell type for H22–Fel d 1 plus TSLP versus H22–Fel d 1 alone (left) and H22–Fel d 1 plus TSLP versus TSLP alone (right; n = 5 per group). Error bars represent 95% CIs. ∗Significant after adjusting for multiple comparisons. C, Representative dot plot from a patients with AD showing the phenotype of gated CD4+ T cells induced by different stimuli. NS, Nonstimulated. Journal of Allergy and Clinical Immunology 2010 125, 247-256.e8DOI: (10.1016/j.jaci.2009.10.027) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 The TH2-promoting effect of coprimed moDCs is OX40L-independent. A, Expression of OX40L on moDCs after priming with different stimuli for 48 hours. Bars represent the mean fluorescence intensity (MFI) ± SEM (n = 5 subjects per group). ∗P < .05. B, Effect of anti-OX40L mAb on the percentage of IL-4+ T cells induced (day 10) by atopic moDCs primed with different stimuli for 48 hours. Bars represent the means ± SEMs (n = 4 subjects). C, CCL17/TARC levels in supernatants from cultures containing moDCs primed with different stimuli for 48 hours. Bars represent the means ± SEMs (n = 5 subjects per group). Fel, Fel d 1; H-Fel, H22–Fel d 1; NS, nonstimulated. Journal of Allergy and Clinical Immunology 2010 125, 247-256.e8DOI: (10.1016/j.jaci.2009.10.027) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 H22–Fel d 1 enhances TSLPr expression on atopic moDCs. A, Comparison of TSLPr expression on moDCs from atopic and nonatopic subjects. moDCs were primed with different stimuli, and expression of TSLPr was analyzed at 24 hours. Data are representative of 4 atopic and 4 nonatopic subjects. FSC, Forward scatter. B, Time course of TSLPr expression on moDCs (representative of 6 subjects). Solid red histogram corresponds to the fluorescence-minus-one control (FMO). C, TSLPr expression on blood DCs. DCs were isolated, primed with different stimuli, and analyzed for TSLPr expression at 24 hours. Data are representative of 3 experiments. Fel, Fel d 1; H-Fel, H22–Fel d 1; NS, nonstimulated. Journal of Allergy and Clinical Immunology 2010 125, 247-256.e8DOI: (10.1016/j.jaci.2009.10.027) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 FcR signaling components modulate H22–Fel d 1–induced TSLP receptor expression. A, Calcium mobilization in atopic moDCs primed with different stimuli. The y-axis represents the ratio of free to bound calcium. Data are representative of 4 atopic subjects. B, Effect of kinase inhibitors on H22–Fel d 1–induced TSLPr expression in atopic DCs. Cells were incubated with inhibitors for 1 hour before priming with H22–Fel d 1 and analyzing for TSLPr expression (24 hours). Inhibitors tested were PP2 (SRTK inhibitor), piceatannol (Syk kinase inhibitor), and LY294002 (PI3-kinase inhibitor). Data are shown for 8 different atopic patients. ∗P ≤ .05. Fel, Fel d 1; H-Fel, H22–Fel d 1. Journal of Allergy and Clinical Immunology 2010 125, 247-256.e8DOI: (10.1016/j.jaci.2009.10.027) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Blocking TSLPr upregulation in coprimed moDCs abolishes their TH2-promoting effect. Atopic moDCs were incubated with no inhibitor (No inh.) or with LY294002 before priming with different stimuli. Cells were then washed and cultured with CD4+ T cells for 7 days. Intracellular cytokine expression was analyzed by flow cytometry. Dot plots show the phenotype of gated CD4+ T cells. H-Fel, H22–Fel d 1; NS, nonstimulated. Journal of Allergy and Clinical Immunology 2010 125, 247-256.e8DOI: (10.1016/j.jaci.2009.10.027) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Atopic DCs coprimed with H22–Fel d 1 and TSLP induce enhanced secretion of TH2 cytokines. MoDCs isolated from subjects with cat allergy with and without AD were cocultured with CD4+ T cells after priming for 48 hours with Fel d 1 (Fel), H22–Fel d 1 (H-Fel), TSLP, or H22–Fel d 1 plus TSLP. Secreted cytokines were measured on day 10. Bars represent means ± SEMs (n = 5 per group). ∗Significant after adjusting for multiple comparisons. NS, Nonstimulated. Journal of Allergy and Clinical Immunology 2010 125, 247-256.e8DOI: (10.1016/j.jaci.2009.10.027) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Representative data showing the effect of anti-OX40L antibody on T-cell responses induced by atopic moDCs. CD4+ T cells were cocultured in the presence or absence of anti-OX40L mAb with moDCs that had been primed for 48 hours with different stimuli. Dot plots show the phenotype of gated CD4+ T cells in the presence or absence of anti-OX40L mAb or isotype control. H-Fel, H22–Fel d 1; NS, nonstimulated. Journal of Allergy and Clinical Immunology 2010 125, 247-256.e8DOI: (10.1016/j.jaci.2009.10.027) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Analysis of the neutralizing capacity of anti-OX40L antibody Analysis of the neutralizing capacity of anti-OX40L antibody. Blood DCs were primed with TSLP for 48 hours before coculture with CD4+ T cells in the presence or absence of anti-OX40L mAb (7 days). A, Frequency of IL-4+ T cells detected in the presence or absence of antibody (Ab). An isotype control had no effect (data not shown). Histogram shows OX40 expression on IL-4+ T cells versus IL-4–negative cells. B, Comparison of OX40L expression on nonstimulated (NS) and TSLP-primed DCs (48 hours). Data are representative of 2 experiments. Journal of Allergy and Clinical Immunology 2010 125, 247-256.e8DOI: (10.1016/j.jaci.2009.10.027) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Change in the percentage of TSLPr+ cells induced by different stimuli in atopic moDCs. MoDCs were primed with different stimuli, and expression of TSLPr was analyzed at 24 hours. ∗P < .05 and ∗∗P < .01 (n = 4 atopic subjects). Fel, Fel d 1; H-Fel, H22–Fel d 1; NS, nonstimulated. Journal of Allergy and Clinical Immunology 2010 125, 247-256.e8DOI: (10.1016/j.jaci.2009.10.027) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Analysis of the effect of human serum on TSLPr expression Analysis of the effect of human serum on TSLPr expression. THP-1 monocytes were primed with H22–Fel d 1 in the presence of FBS or atopic and nonatopic serum, and TSLPr expression was measured at 24 hours. Data are representative of 8 experiments. H-Fel, H22–Fel d 1; FMO, fluorescence-minus-one control. Journal of Allergy and Clinical Immunology 2010 125, 247-256.e8DOI: (10.1016/j.jaci.2009.10.027) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

TSLPr is not induced by low-dose LPS TSLPr is not induced by low-dose LPS. Cells were primed with H22–Fel d 1 or LPS (0.5 ng/mL or 1 μg/mL), and TSLPr expression was analyzed by flow cytometry (mean ± SD for 7 subjects). ∗P < .05. H-Fel, H22–Fel d 1; MFI, mean fluorescent intensity; NS, nonstimulated. Journal of Allergy and Clinical Immunology 2010 125, 247-256.e8DOI: (10.1016/j.jaci.2009.10.027) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions