Increased activation-induced cell death of high IFN-γ–producing TH1 cells as a mechanism of TH2 predominance in atopic diseases Tunc Akkoc, PhD, Pieter.

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Increased activation-induced cell death of high IFN-γ–producing TH1 cells as a mechanism of TH2 predominance in atopic diseases Tunc Akkoc, PhD, Pieter J.A. de Koning, MSc, Beate Rückert, Isil Barlan, MD, Mübeccel Akdis, MD, PhD, Cezmi A. Akdis, MD Journal of Allergy and Clinical Immunology Volume 121, Issue 3, Pages 652-658.e1 (March 2008) DOI: 10.1016/j.jaci.2007.12.1171 Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Increased AICD in PBMCs and CD45RO+ T cells in AD. A, PBMCs were stimulated with anti-CD3 mAb for 48 hours. Results represent means ± SDs of 5 atopic and 9 healthy donors (∗P < .002). B, PBMCs were stimulated with 20 μg/mL anti-CD3 for 48 hours (∗P < .002). C, Spontaneous cell death of CD45RO+ T cells was analyzed after 48 hours (∗P < .05). Journal of Allergy and Clinical Immunology 2008 121, 652-658.e1DOI: (10.1016/j.jaci.2007.12.1171) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Increased activation-induced cell death of TH1 cells in AD. CD45RA+ T cells were driven to TH1 and TH2 cells for 5 days. The quadrants are set by gating 100% viable cells and 100% dead cells. Means ± SDs of apoptotic cells are shown in each quadrant. (∗P < .05 between TH1 and TH2 in both groups, °P < .05 between TH1 of both groups). Journal of Allergy and Clinical Immunology 2008 121, 652-658.e1DOI: (10.1016/j.jaci.2007.12.1171) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Increased expression of Fas, Fas-ligand, and TNFR-II on T cells of patients with AD. Peripheral blood–derived CD45RA+ T cells from atopic and healthy individuals cultured in in vitro differentiation conditions to TH1 and TH2 cells for 6 days. Data represent 1 out of 3 experiments with similar results (∗P < .001). IC, Isotype control. Journal of Allergy and Clinical Immunology 2008 121, 652-658.e1DOI: (10.1016/j.jaci.2007.12.1171) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 High IFN-γ–expressing T cells undergo AICD in atopy. A, Purification of IFN-γ–secreting and IFN-γ–nonsecreting CD4+ T cells. B, Increased expression of Fas and Fas-ligand on purified IFN-γ–secreting CD4+ T cells in patients with AD. C, IFN-γ–secreting CD4+ T cells of atopic patients showed increased apoptosis compared with healthy subjects and IFN-γ–nonsecreting CD4+ T cells (∗P < .01). D, Purified CD4+ IL-4–secreting T cells. IC, Isotype control; Fas-L, Fas-ligand. Journal of Allergy and Clinical Immunology 2008 121, 652-658.e1DOI: (10.1016/j.jaci.2007.12.1171) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 IFN-γ plays an essential role in TH1 cell AICD in atopic diseases. A, TH1 cells from atopic donors were cultured with anti–IFN-γ, anti–TNF-α, anti–IL-12, or IL-4 and stimulated with mAb against CD2, CD3, and CD28 for 4 days. B, TH1 cells from atopic donors were stimulated with anti-CD2/CD3/CD28 mAbs in the presence of different doses of anti–IFN-γ, anti–TNF-α, soluble Fas-Fc (sFas-Fc), the combination of 5 μg/mL anti–IFN-γ and titrated amounts of sFas-Fc, and isotype control mAb (∗P < .001 for the sum of early and late apoptotic cells compared with nonneutralizing conditions; #P < .05 compared to without sFas-Fc). C, IFN-γ–expressing but not IL-13–expressing T cells show active caspase-3 expression. Data represent 1 of 3 independent experiments. IC, Isotype control; u.s., unstimulated. Journal of Allergy and Clinical Immunology 2008 121, 652-658.e1DOI: (10.1016/j.jaci.2007.12.1171) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Increased apoptosis of CXCR3+ T cells in atopic dermatitis. A, PBMCs of patients with AD and healthy donors are labeled with antihuman CXCR3-phycoerythrin mAb. Apoptotic cells are measured immediately after purification and on day 3 (∗P < .05). B, CXCR3+T cells are purified with antiphycoerythrin microbeads after phycoerythrin labeling of CXCR3+ T cells from PBMCs. Unstimulated cultures are analyzed on day 3 (∗P < .05). Journal of Allergy and Clinical Immunology 2008 121, 652-658.e1DOI: (10.1016/j.jaci.2007.12.1171) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions