Forkhead box protein 3 demethylation is associated with tolerance induction in peanut- induced intestinal allergy Meiqin Wang, MD, PhD, Ivana V. Yang,

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Forkhead box protein 3 demethylation is associated with tolerance induction in peanut- induced intestinal allergy Meiqin Wang, MD, PhD, Ivana V. Yang, PhD, Elizabeth J. Davidson, BS, Anthony Joetham, BS, Katsuyuki Takeda, MD, PhD, Brian P. O'Connor, PhD, Erwin W. Gelfand, MD Journal of Allergy and Clinical Immunology Volume 141, Issue 2, Pages 659-670.e2 (February 2018) DOI: 10.1016/j.jaci.2017.04.020 Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Oral PE administration in pups before sensitization induces tolerance to peanut protein. A, Protocol for induction of peanut allergy and induction of tolerance to peanut protein. PE was fed to pups from day −28 to day −15. Sensitization was performed on days 1, 7, and 21. Challenge was performed from day 35 to day 41. B, Kinetics of the development of diarrhea after feeding PE before sensitization. C, Scores based on the severity of clinical signs were assessed 30 minutes after oral challenge. D, Serum levels of peanut-specific IgE, IgG1, and IgG2a were assessed by ELISA 24 hours after the last challenge and expressed as OD of diluted serum. Results were obtained from 3 individual experiments with 4 mice per group. **P < .01 and #P < .001. n.s., Not significant. PBS/PBS/PE, Sham-fed and sham-sensitized and peanut challenged; PBS/PE/PE, sham-fed and peanut sensitized and challenged; PE0.05/PE/PE, fed low doses of PE and PE sensitized and challenged; PE0.5/PE/PE, fed high doses of PE and PE sensitized and challenged. Journal of Allergy and Clinical Immunology 2018 141, 659-670.e2DOI: (10.1016/j.jaci.2017.04.020) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Numbers of Treg cells and FoxP3 expression in MLN CD4+ T cells and jejunum. A, Foxp3 mRNA expression detected by quantitative RT-PCR in MLN CD4+ T cells from PBS/PBS/PE, PBS/PE/PE, PE0.05/PE/PE, and PE0.5/PE/PE mice. B, Mucosal FoxP3-expressing cells were identified after immunohistochemical staining with anti-FoxP3 antibody. Representative sections of PBS/PBS/PE mice (a), PBS/PE/PE mice (b), PE0.05/PE/PE mice (c), and PE0.5/PE/PE mice (d) are shown. C, Quantitation of mucosal FoxP3-expressing cells. D, Representative flow cytometric analysis of the percentage of FoxP3-expressing cells among the CD4+CD25+ T cells from MLNs. Results were obtained from 3 individual experiments with 4 mice per group. SSC, Side scatter; FSC, forward scatter. Magnification ×200. *P < .05 and **P < .01. n.s., Not significant. Journal of Allergy and Clinical Immunology 2018 141, 659-670.e2DOI: (10.1016/j.jaci.2017.04.020) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Effects of tolerance induction on cytokine expression in MLN CD4+ T cells and jejunum. A, Ifng, Il10, Il13, Il17a, and Tgfβ mRNA expression in jejunum. B, Tbx21 (T-bet), Gata3, and RORγt expression in jejunum. C, Representative flow cytometric analysis of TH1, TH2, and TH17 cytokine expression in CD4+ T cells from MLNs. Results were from 3 independent experiments. SSC, Side scatter; FSC, forward scatter. *P < .05 and **P < .01. n.s., Not significant. Journal of Allergy and Clinical Immunology 2018 141, 659-670.e2DOI: (10.1016/j.jaci.2017.04.020) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 DC subsets in MLNs. Cells from MLNs were stained with antibodies to identify DC subsets. The populations were gated on 4′, 6-diamidino-2-phenylindole–negative and B220− cells. The CD11c+MHCIIhigh population was further characterized on the basis of CD103 and CD11b expression. Results are from 2 independent experiments. *P < .05, **P < .01, and #P < .001. n.s., Not significant. Journal of Allergy and Clinical Immunology 2018 141, 659-670.e2DOI: (10.1016/j.jaci.2017.04.020) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Antigen-specific suppressive function of CD4+CD25+ cells. CFSE-labeled MNCs from PE- or OVA-immunized BALB/c mice were cocultured with CD4+CD25+ MLN cells from tolerant mice in the presence or absence of PE (200 μg/mL) or OVA (10 μg/mL) for 5 days. CFSE fluorescence intensities were monitored by using flow cytometry. Results from 2 independent experiments carried out in triplicate are shown. *P < .05 and **P < .01. n.s., Not significant. Journal of Allergy and Clinical Immunology 2018 141, 659-670.e2DOI: (10.1016/j.jaci.2017.04.020) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Anti-CD25 administration attenuates oral tolerance. A, Protocol for induction of tolerance to peanut protein and treatment with anti-CD25. Anti-CD25 was administered to pups on days −21, −1, and 20. B, Kinetics of the development of diarrhea in peanut-tolerant mice treated with anti-CD25 or control IgG. C, Scores based on the severity of clinical signs were assessed 30 minutes after oral challenge. D, Serum levels of peanut-specific IgE, IgG1, and IgG2a were assessed by using ELISA 24 hours after the last challenge and expressed as the OD of diluted serum. E, Representative flow cytometric analysis of the percentage of FoxP3-expressing cells among the CD4+CD25+ T cells from MLNs of tolerant mice treated with anti-CD25 or control IgG. SSC, Side scatter; FSC, forward scatter. F, Representative flow cytometric analysis of the percentage of CD4+CD25+ T cells in spleens and peripheral blood from tolerant mice treated with anti-CD25 or control IgG. G, Ifng, Il10, Il13, Il17a, and Tgfb mRNA expression in jejunum of tolerant mice treated with anti-CD25 or control IgG. H, Tbx21 (T-bet), Gata3, and RORγt expression in jejunum of tolerant mice treated with anti-CD25 or control IgG. Results were obtained from 2 individual experiments with 4 mice per group. *P < .05, **P < .01, and #P < .001. n.s., Not significant. Journal of Allergy and Clinical Immunology 2018 141, 659-670.e2DOI: (10.1016/j.jaci.2017.04.020) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Anti-CD25 administration attenuates oral tolerance. A, Protocol for induction of tolerance to peanut protein and treatment with anti-CD25. Anti-CD25 was administered to pups on days −21, −1, and 20. B, Kinetics of the development of diarrhea in peanut-tolerant mice treated with anti-CD25 or control IgG. C, Scores based on the severity of clinical signs were assessed 30 minutes after oral challenge. D, Serum levels of peanut-specific IgE, IgG1, and IgG2a were assessed by using ELISA 24 hours after the last challenge and expressed as the OD of diluted serum. E, Representative flow cytometric analysis of the percentage of FoxP3-expressing cells among the CD4+CD25+ T cells from MLNs of tolerant mice treated with anti-CD25 or control IgG. SSC, Side scatter; FSC, forward scatter. F, Representative flow cytometric analysis of the percentage of CD4+CD25+ T cells in spleens and peripheral blood from tolerant mice treated with anti-CD25 or control IgG. G, Ifng, Il10, Il13, Il17a, and Tgfb mRNA expression in jejunum of tolerant mice treated with anti-CD25 or control IgG. H, Tbx21 (T-bet), Gata3, and RORγt expression in jejunum of tolerant mice treated with anti-CD25 or control IgG. Results were obtained from 2 individual experiments with 4 mice per group. *P < .05, **P < .01, and #P < .001. n.s., Not significant. Journal of Allergy and Clinical Immunology 2018 141, 659-670.e2DOI: (10.1016/j.jaci.2017.04.020) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 FoxP3 DNA methylation in MLN CD4+ T cells. FoxP3 methylation detected by means of bisulfite pyrosequencing was assayed in genomic DNA from MLN CD4+ T cells; 9 CpG sites within the TSDR were examined. Results were obtained from 2 independent experiments. *P < .05 and **P < .01. n.s., Not significant. Journal of Allergy and Clinical Immunology 2018 141, 659-670.e2DOI: (10.1016/j.jaci.2017.04.020) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 DCs in MLNs. Populations were gated on 4′, 6-diamidino-2-phenylindole (DAPI)–negative and B220− cells. The CD11c+MHCIIhigh population was characterized further based on CD103 and CD11b expression. Journal of Allergy and Clinical Immunology 2018 141, 659-670.e2DOI: (10.1016/j.jaci.2017.04.020) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Mouse Foxp3 gene structure and DNA methylation target CpG sites at CNS2 of the first intron of the Foxp3 gene (adapted from EpigenDx; Assay ID: ADS568). Journal of Allergy and Clinical Immunology 2018 141, 659-670.e2DOI: (10.1016/j.jaci.2017.04.020) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions