Activated glycoprotein A repetitions predominant (GARP)–expressing regulatory T cells inhibit allergen-induced intestinal inflammation in humanized mice

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Activated glycoprotein A repetitions predominant (GARP)–expressing regulatory T cells inhibit allergen-induced intestinal inflammation in humanized mice Melanie Eschborn, MSc, Benno Weigmann, PhD, Sonja Reissig, PhD, Ari Waisman, PhD, Joachim Saloga, MD, Iris Bellinghausen, PhD Journal of Allergy and Clinical Immunology Volume 136, Issue 1, Pages 159-168 (July 2015) DOI: 10.1016/j.jaci.2015.04.020 Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Inhibition of total and allergen-specific human IgE production in humanized NOD-scid-γc−/− mice by coinjection of autologous Treg cells. 1 × 107 PBMCs were injected intraperitoneally with or without the respective allergen in the presence or absence of (0.5-1) × 106 autologous CD4+CD25+ Treg cells. Three weeks later, total and allergen-specific human IgE and IgG4 level was measured in murine sera by ImmunoCAP test or ELISA. Shown are the single values + mean of 14 (10 for IgG4) experiments. A, Allergen; aTreg, activated Treg. Journal of Allergy and Clinical Immunology 2015 136, 159-168DOI: (10.1016/j.jaci.2015.04.020) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Allergen-specific gut inflammation in human PBMC-engrafted NOD-scid-γc−/− mice is inhibited by coinjection of autologous Treg cells. Three weeks after PBMC ± Treg-cell engraftment, mice were examined with a video mini-endoscope before and after rectal allergen challenge. Shown are the endoscopic pictures and the histology (magnification ×100) of a representative result (A) and the single values + mean of the endoscopic score out of 14 (B) or 5 (C) experiments with generally 2 mice per group. D, Staining of the colon with anti-human CD45 (magnification ×40) or anti-human FoxP3 (magnification ×400) after rectal challenge. E, Staining of the spleen with the indicated markers, mean ± SEM of 13 experiments. A, Allergen; aTreg, activated Treg; H&E, hematoxylin and eosin. *P ≤ .05 compared with PBMC + allergen. Journal of Allergy and Clinical Immunology 2015 136, 159-168DOI: (10.1016/j.jaci.2015.04.020) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Coinjection of autologous Treg cells inhibits allergen-specific proliferation and cytokine production in vitro. Three weeks after PBMC ± Treg-cell engraftment, human CD4+ T cells were recovered from spleens and stimulated with autologous unpulsed (DC medium), allergen-pulsed (DC allergen), or tetanus toxoid–pulsed DC (DC TT) to analyze their proliferation and cytokine production. Shown is the mean ± SEM of 8 experiments. A, Allergen; aTreg, activated Treg. *P ≤ .05 compared with PBMC + Allergen. Journal of Allergy and Clinical Immunology 2015 136, 159-168DOI: (10.1016/j.jaci.2015.04.020) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Comparison of GARP expression and the effect of its depletion on differently activated Treg cells. A, CD4+ T cells were activated with anti-human CD3/CD28 or allergen-pulsed DC for 48 hours. Shown is the mean ± SEM of FoxP3 and GARP expression of CD25+CD4+ T cells (n = 5). B, Endoscopic score of PBMC ± Treg-cell–engrafted mice after rectal allergen challenge. Shown is the mean ± SEM of 6 experiments, *P ≤ .001 compared with no Treg cell. C, Staining of DC-activated Treg cells before (left panel) and after depletion of GARP (right panel). D, Suppression of DC-stimulated CD4+CD25− effector T-cell (Teff) proliferation by differentially activated Treg cells. Shown is the mean ± SEM of 4 experiments. A, Allergen; FITC, fluorescein isothiocyanate. *P ≤ .01 compared with Teff. §P ≤ .05 compared with untreated Treg cells. Journal of Allergy and Clinical Immunology 2015 136, 159-168DOI: (10.1016/j.jaci.2015.04.020) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Depletion of GARP-expressing Treg cells after their activation abolishes inhibition of allergen-specific gut inflammation. Mice were treated with PBMCs ± activated Treg cells or GARP-depleted Treg cells on day 0 or during allergen boost on day 8 and challenged as described in Fig 2. Anti-human GARP mAb 7B11 or mouse IgG2b isotype control was also applied together with Treg-cell injection. Shown are the single values + mean of total and allergen-specific human IgE in murine sera out of 6 experiments (A), the endoscopic pictures and hematoxylin and eosin staining (magnification ×100) of a representative result (B), and the single values + mean (C and D) of the endoscopic score out of 7 (4 for D) experiments. A, Allergen; aTreg, activated Treg. Journal of Allergy and Clinical Immunology 2015 136, 159-168DOI: (10.1016/j.jaci.2015.04.020) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Administration of GARP enhances Treg-cell numbers and prevents allergen-specific gut inflammation. Mice were treated with PBMCs ± recombinant GARP or activated Treg cells and challenged as described in Fig 2. Shown are the single values + mean of total human IgE (A), the endoscopic pictures, hematoxylin and eosin (magnification ×100), anti-human CD45 (magnification ×100), and anti-human FoxP3 staining of the colon (magnification ×400) of a representative result (B), and the single values + mean of the endoscopic score (C) out of 5 experiments. A, Allergen; aTreg, activated Treg; H&E, hematoxylin and eosin. Journal of Allergy and Clinical Immunology 2015 136, 159-168DOI: (10.1016/j.jaci.2015.04.020) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions