IL-4 confers resistance to IL-27–mediated suppression on CD4+ T cells by impairing signal transducer and activator of transcription 1 signaling Zhihong.

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IL-4 confers resistance to IL-27–mediated suppression on CD4+ T cells by impairing signal transducer and activator of transcription 1 signaling Zhihong Chen, MD, PhD, Shanze Wang, MD, PhD, Nkiruka Erekosima, MPH, MD, Yapeng Li, PhD, Jessie Hong, PhD, Xiaopeng Qi, PhD, Patricia Merkel, MS, Vijaya Nagabhushanam, MD, PhD, Eugene Choo, MD, Rohit Katial, MD, Rafeul Alam, MD, PhD, Anita Trikha, MD, Hong Wei Chu, MD, Yonghua Zhuang, MD, PhD, Meiling Jin, MD, Chunxue Bai, MD, PhD, Hua Huang, MD, PhD Journal of Allergy and Clinical Immunology Volume 132, Issue 4, Pages 912-921.e5 (October 2013) DOI: 10.1016/j.jaci.2013.06.035 Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Human IL-27 suppresses TH2 cell differentiation independent of IFN-γ and IL-10. ELISA analysis of IL-4 protein produced by human CD4+ T cells primed with conditions indicated. Neu, Neutralizing conditions; Th2, TH2-inducing conditions. A, Means ± SDs (n = 4). B, Data are representative of 2 independent experiments with similar results. C, Healthy volunteers (n = 6) and allergic asthmatic patients (n = 6). Each symbol represents the result from 1 subject. ns, Not significant. Journal of Allergy and Clinical Immunology 2013 132, 912-921.e5DOI: (10.1016/j.jaci.2013.06.035) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Repeated exposure to TH2-inducing conditions induces IL-27 resistance. A, ELISA analysis of IL-4 produced by healthy human CD4+ T cells subjected to 2 rounds of priming. B, ELISA analysis of IL-4 produced by mouse CD4+ T cells primed as indicated. Error bars and statistical analysis are described in the Methods section in this article's Online Repository. Data represent 2 independent experiments with similar results. ns, Not significant. Journal of Allergy and Clinical Immunology 2013 132, 912-921.e5DOI: (10.1016/j.jaci.2013.06.035) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 High doses of mouse IL-4, but not IL-2, induces IL-27 resistance after just 1 round of priming. A and B, ELISA analysis of IL-4 produced by mouse CD4+ T cells that were primed with increasing doses of recombinant murine IL-4 (Fig 3, A) and increasing doses of rhIL-2 (Fig 3, B). C, The rest of the TH2-inducing conditions are identical to those described for the TH2int conditions (see the Methods section). IL-27 resistance was measured in CD4+ T cells that were primed under TH2lo, TH2int, and TH2hi conditions. The percentages on the top of the white bars indicate the percentage of reduction in IL-4 production. Data are representative of 4 (Fig 3, A) or 2 (Fig 3, B and C) independent experiments with similar results. ns, Not significant. Journal of Allergy and Clinical Immunology 2013 132, 912-921.e5DOI: (10.1016/j.jaci.2013.06.035) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 The high concentrations of TH2-inducing reagents specifically impair STAT1 phosphorylation. A and B, Intracellular staining of IL-4 and IFN-γ protein in cells primed under TH2int conditions for 5 days. C, Western analysis of STAT1 phosphorylation in cultured CD4+ T cells. Densitometer measurements of ΔpSTAT1/STAT1 are shown in the right panel. ΔpSTAT1/STAT1 = [pSTAT1/STAT1 in IL-27–stimulated cells] − [pSTAT1/STAT1 in nonstimulated cells]. D, Western analysis of STAT3 and STAT4 phosphorylation. Neu, Neutralizing conditions. Data are representative of 2 (Fig 4, A, B, and D) or 6 (Fig 4, C) independent experiments with similar results. Journal of Allergy and Clinical Immunology 2013 132, 912-921.e5DOI: (10.1016/j.jaci.2013.06.035) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 STAT1 phosphorylation is inhibited in TH2m cells of allergic asthmatic patients. A, Fluorescence-activated cell sorting analysis of STAT1 phosphorylation (pSTAT1) in various subsets of CD4+ T cells. Naive, Naive CD4+ T cells; non-TH2m, memory non-TH2 cells; TH2m, memory TH2 cells. B, Fluorescence-activated cell sorting analysis of pSTAT6. C, ΔMFIs of pSTAT1 in gated cell populations (patients [P], n = 6; control subjects [C], n = 6). D, ΔMFIs of pSTAT6 (patients [P], n = 6; control subjects [C], n = 6). ns, Not significant. Journal of Allergy and Clinical Immunology 2013 132, 912-921.e5DOI: (10.1016/j.jaci.2013.06.035) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 High concentrations of TH2-inducing reagents upregulate SOCS3 expression in mouse CD4+ T cells cultured for 5 days. A and B, qPCR analysis (Fig 6, A) and Western blot analysis (Fig 6, B). The right panel of Fig 6, B, indicates densitometer measurements. HSP70, Heat shock protein 70. C, Small interfering Socs3 RNA knockdown efficiency. D, Western blot analysis of pSTAT1/STAT1 in cultured CD4+ T cells. The bottom panel indicates densitometer measurements. E, IL-4 production by small interfering Socs3 knocked down in cultured CD4+ T cells. Data are representative of 2 independent experiments with similar results. Neu, Neutralizing conditions; ns, not significant. Journal of Allergy and Clinical Immunology 2013 132, 912-921.e5DOI: (10.1016/j.jaci.2013.06.035) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 SOCS3 expression is increased in CD4+ T cells of allergic asthmatic patients. A, qPCR analysis of SOCS mRNA in human CD4+ T cells (healthy control subjects, n = 10; patients with allergic asthma, n = 12). B, Western blot analysis. The bottom panel shows densitometer measurements. A, Patients with allergic asthma (n = 6); H, healthy control subjects (n = 6); HSP70, heat shock protein 70; ns, not significant. Journal of Allergy and Clinical Immunology 2013 132, 912-921.e5DOI: (10.1016/j.jaci.2013.06.035) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 The TH2hi-primed TH2 cells do not lack the IL-27R. Naive mouse CD4+ T cells were cultured under neutralizing conditions or TH2hi conditions for 5 days. RNA was prepared from the resultant cells, and qPCR was performed. SDs were derived from triplicate measurements of 1 representative experiment. Data are representative of 2 independent experiments with similar results. Neu, Neutralizing conditions; ns, not significant. Journal of Allergy and Clinical Immunology 2013 132, 912-921.e5DOI: (10.1016/j.jaci.2013.06.035) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions