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Oliver T. Burton, PhD, Jaciel M. Tamayo, PhD, Amanda J

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1 Allergen-specific IgG antibody signaling through FcγRIIb promotes food tolerance 
Oliver T. Burton, PhD, Jaciel M. Tamayo, PhD, Amanda J. Stranks, DPhil, Kyle J. Koleoglou, Hans C. Oettgen, MD, PhD  Journal of Allergy and Clinical Immunology  Volume 141, Issue 1, Pages e3 (January 2018) DOI: /j.jaci Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Effect of IgG on food allergen sensitization. A, Anaphylaxis: core body temperature decrease after enteral OVA challenge of sensitized BALB/c background Il4raF709 mice (n = 4 for saline and n = 5 for OVA and OVA plus IgG). B, Serum OVA-specific IgE. n.d., Not detected. C, Levels of the mast cell granule protease MMCP-1 in challenged mice. D, Serum IL-4 levels after challenge. E, Intestinal mast cell numbers. F and G, Small intestinal TH2 cell (Fig 1, F) and Treg cell (Fig 1, G) frequencies. Data shown are from one of 3 independent experiments. *P < .05, **P < .01, ***P < .001, and ****P < .0001. Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 Effect of exogenous IgG on allergen desensitization. A, Anaphylaxis in OVA-sensitized and desensitized Il4raF709 mice on the BALB/c background after challenge (n = 4 for sensitized only, n = 5 for OVA + control IgG, and n = 4 for OVA + αOVA IgG). B, MMCP-1 release. C, IL-4 release. D, Intestinal mast cell numbers. E, OVA-specific IgE levels. F, Intestinal Treg cell frequencies. G, Intestinal TH2 cell frequencies. Data shown are representative of 3 independent experiments. *P < .05, **P < .01, ***P < .001, and ****P < .0001. Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 Role of FcγRIIb in allergic sensitization. A, Anaphylaxis in OVA-sensitized Il4raF709 and Il4raF709 FcγRIIb−/− mice on the C56BL/6 background. B, IL-4 release. C, Intestinal mast cell numbers. D, Specific IgE levels. E, Intestinal Treg cell frequencies. F, Intestinal TH2 cell frequencies. Fig 3, A, C, and E, n = 3; Fig 3, B, D, and F, n = 4 for wild-type (WT) and n = 5 for FcγRIIb−/−. Data shown are representative of 3 independent experiments. *P < .05, ***P < .001, and ****P < .0001. Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 Role of IgG and FcγRIIb and in tolerance restoration during desensitization. A, Anaphylaxis after enteral challenge in OVA-sensitized and desensitized Il4raF709 and Il4raF709 FcγRIIb−/− mice on the C57BL/6 background. ns, Not significantly different. B, Serum IL-4 levels. C, Intestinal mast cells. D, Specific IgE levels. E, Intestinal Treg cell frequencies. F, Intestinal TH2 cell frequencies. n = 4-5 for wild-type (WT) control IgG, n = 3-4 for WT αOVA IgG, n = 4-5 for FcγRIIb−/− control IgG, and n = 4-5 for FcγRIIb−/− αOVA IgG. Data shown are from one of 2 independent experiments. **P < .01, ***P < .001, and ****P < .0001. Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 5 Effect of mast cell FcγRIIb ligation on development of Treg cell responses during sensitization. A, Anaphylaxis in Il4raF709 KitW-sh mice on the C57BL/6 background reconstituted with wild-type (WT) or FcγRIIb−/− mast cells (MC; n = 3 for F709 KitW-sh No MC, n = 5 for WT MC, n = 4 for WT MC αOVA IgG, n = 4 for FcγRIIb−/− MC, and n = 5 for FcγRIIb−/− MC αOVA IgG). B, Serum IL-4 levels after challenge. C, Serum OVA-specific IgE (n = 6 for F709 KitW-sh No MC, n = 8 for WT MC, n = 8 for WT MC αOVA IgG, n = 8 for FcγRIIb−/− MC, and n = 9 for FcγRIIb−/− MC αOVA IgG). D, Intestinal mast cells. E, Proportional representation of Treg cells in the small intestine. F, Intestinal TH2 cell frequencies. Data shown are from one of 3 independent experiments. *P < .05, **P < .01, ***P < .001, and ****P < .0001. Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig 6 Requirement for FcγRIIb in IgG-mediated suppression of IgE:FcεRI-triggered IL-4 expression. A, Supernatant levels of IL-4 in wild-type (WT) and FcγRIIb-deficient murine mast cells (C57BL/6 background, n = 3) sensitized with polyclonal IgE αOVA and stimulated with OVA in the presence of monoclonal IgG2a αOVA. B, IL-13 secretion. C, mRNA levels of IL4 in human mast cells (n = 3) sensitized with IgE α peanut (αPN) and stimulated with peanut in the presence of IgG αPN and/or αFcγRII (CD32) blocking antibody. D, IL-4 secretion by human mast cells. Data are representative of 3 independent experiments. **P < .01, ***P < .001, and ****P < .0001. Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Fig 7 IL-4 administration partially reverses IgG-mediated inhibition of allergic responses. A, Anaphylaxis in Il4raF709 mice (n = 5) on the BALB/c background sensitized to OVA in combination with IgG αOVA, IL-4, or both. B, Specific IgE levels. ns, Not significantly different. C, MMCP-1 release in serum. D, Serum IL-4 levels. E, Intestinal mast cell numbers. F, Intestinal TH2 cell frequencies. G, Intestinal Treg cell frequencies. Data are representative of 3 independent experiments. *P < .05, **P < .01, ***P < .001, and ****P < .0001. Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 Fig E1 Anti-OVA immunoglobulin levels in sera of OVA-sensitized Il4raF709 mice with or without FcγRIIb, as determined by means of ELISA. *P < .05 and ****P < .0001 by using the unpaired t test on log-transformed values. Data are representative of 3 independent experiments. WT, Wild-type. Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

10 Fig E2 Intestinal mast cell reconstitution in Il4raF709 KitW-sh mice. Flow cytometric analysis of jejunal lamina propria leukocytes showing c-Kit+IgE+ mast cells in mice engrafted with wild-type (WT) or FcγRIIb−/− mast cells carrying the Il4raF709 mutation. All mice were subjected to OVA sensitization, and some were additionally administered IgG anti-OVA. Representative flow plots are shown, gating on viable CD45+ leukocytes. Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

11 Fig E3 Detection of secreted IL-4 is enhanced in the absence of IL-4Rα–mediated uptake. BALB/c or IL-4Rα−/− murine BMMCs (2 × 105) were cultured for 48 hours, and IL-4 levels in the supernatant were determined by means of ELISA. For IgE/antigen (Ag) stimulation, cells were sensitized with polyclonal IgE αOVA from allergic mouse serum and then stimulated with 1 μg/mL OVA. PI, Phorbol 12,13-dibutyrate and ionomycin (500 ng/mL each); WT, wild-type. *P < .05, ***P < .001, and ****P < .0001, Bonferroni posttest on ANOVA. Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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