Critical role of IL-21 in modulating TH17 and regulatory T cells in Behçet disease Guillaume Geri, MSc, MD, Benjamin Terrier, MSc, MD, Michelle Rosenzwajg,

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Critical role of IL-21 in modulating TH17 and regulatory T cells in Behçet disease Guillaume Geri, MSc, MD, Benjamin Terrier, MSc, MD, Michelle Rosenzwajg, MD, PhD, Bertrand Wechsler, MD, Maxime Touzot, MSc, MD, Danielle Seilhean, MD, PhD, Tu-Anh Tran, MD, PhD, Bahram Bodaghi, MD, PhD, Lucile Musset, MD, Vassili Soumelis, MD, PhD, David Klatzmann, MD, PhD, Patrice Cacoub, MD, David Saadoun, MD, PhD Journal of Allergy and Clinical Immunology Volume 128, Issue 3, Pages 655-664 (September 2011) DOI: 10.1016/j.jaci.2011.05.029 Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Increased TH17 effectors and decreased FoxP3+CD25hiCD127− Treg cells in BD. Representative dot plots of IL-17A– (A) and IFN-γ (C)–producing CD4+ after gating on CD3+. Frequencies of IL-17A– (B) and IFN-γ (D)–producing T cells from 20 HDs, 25 patients with aBD, and 20 resting patients with BD. Analysis of IL-17A and IFN-γ production by CD4+ T cells according to CD25 expression (E). Frequencies of Treg cells (F). Dot plots (G) and frequencies (H) of resting (box I) and activated Treg cells (box II). ∗P < .05; ∗∗P < .01; ∗∗∗P < .001. Journal of Allergy and Clinical Immunology 2011 128, 655-664DOI: (10.1016/j.jaci.2011.05.029) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Sera from patients with BD contains increased IL-21 level and modulates predominant TH17 cytokines modulating TH1 and TH17 differentiation and FoxP3 expression in HDs. Frequencies of IL-17A+, IFN-γ+, and FoxP3+ cells among sorted CD4+ T cells after 5 days culture with anti-CD3/anti-CD28 and with increasing concentrations of sera (A) in patients with aBD and 20 patients with rBD (3 independent experiments). TH17 cytokine levels in the sera of HDs, patients with aBD, and those with rBD (B). TH1, TH2, and TH17 cytokine levels in culture supernatants in BD (C). Cytokines were assessed in 20 HDs, 25 patients with aBD, and 20 patients with rBD, except for IL-23 and TGF-β, which were assessed in 10 HDs, 18 patients with aBD, and 18 patients with rBD. ∗P < .05; ∗∗P < .01; ∗∗∗P < .001. Journal of Allergy and Clinical Immunology 2011 128, 655-664DOI: (10.1016/j.jaci.2011.05.029) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 IL-21 is produced by central memory CD4+ T cells and correlates with TH17 response and FoxP3 expression. Dot plots (A) and frequencies of IL-21–producing CD4+ T cells (B) after PMA/ionomycin stimulation. IL-21+ is produced by central memory CD4+ T cells (C). Dot plot of IL-21–, IL-17A–, and IFN-γ–producing CD4+ T cells after PMA/ionomycin stimulation (D). Correlations between IL-21–producing CD4+ T cells and TH17 cells (E) and FoxP3+ Tregs (F). ∗P < .05; ∗∗P < .01; ∗∗∗P < .001. Journal of Allergy and Clinical Immunology 2011 128, 655-664DOI: (10.1016/j.jaci.2011.05.029) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Increased production of IL-21, IL-17A, and IFN-γ in the CSF from patients with BD with CNS flare. IL-6 and IL-21 levels in the CSF from control and patients with BD with (BD CNS+) or without (BD CNS−) CNS involvement (A). Dot plots (B) and frequencies (C) of IL-17A– and IFN-γ–producing T cells after PMA/ionomycin stimulation in the peripheral blood and CSF from patients with BD with CNS involvement. Journal of Allergy and Clinical Immunology 2011 128, 655-664DOI: (10.1016/j.jaci.2011.05.029) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Strong IL-21 and IL-17A expression in CNS inflammatory lesions from patients with BD. Immunohistochemical analysis of IL-21, IL-17A, CCL20, CXCL8, and IL-6 expression in the choroid plexus from patients with aBD and from HDs (A). IL-17A and IL-21 are expressed in intracerebral blood vessels from patients with BD (B). IL-17A and IL-21 are expressed in inflammatory brain lesions and colocalized with CD3 in patients with aBD with CNS involvement (C). Journal of Allergy and Clinical Immunology 2011 128, 655-664DOI: (10.1016/j.jaci.2011.05.029) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 IL-21 is critical in modulating TH17 response and FoxP3 expression in BD. Dot plots (A) and frequencies of IL-17A (B) and IFN-γ (C)–producing cells and FoxP3+ expression (D, E) in purified CD4+ T cells in patients with aBD and in HDs after anti-CD3/CD28 stimulation with and without IL-21. IL-21 promotes TH17 and TH1 differentiation in CD4+CD25+ T cells and exclusively promotes TH17 differentiation in CD4+CD25++ T cells (F). Histograms are representative of 5 patients in at least 3 independent experiments. ∗P < .05; ∗∗P < .01; ∗∗∗P < .001. Journal of Allergy and Clinical Immunology 2011 128, 655-664DOI: (10.1016/j.jaci.2011.05.029) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 Blockade of IL-21 with IL-21R/Fc restores effector and regulatory T cells homeostasis. Dot plots (A, B) and histograms (C) of IL-17A and IFN-γ production and FoxP3 expression (B) in purified CD4+ T cells after anti-CD3/anti-CD28 stimulation with and without IL-21 or IL-21R/Fc in patients with aBD. Data are representative of 3 independent experiments in 3 patients with aBD. Journal of Allergy and Clinical Immunology 2011 128, 655-664DOI: (10.1016/j.jaci.2011.05.029) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions