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Dawn C. Newcomb, PhD, Madison G

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1 Human TH17 cells express a functional IL-13 receptor and IL-13 attenuates IL-17A production 
Dawn C. Newcomb, PhD, Madison G. Boswell, BS, Weisong Zhou, PhD, Matthew M. Huckabee, BE, Kasia Goleniewska, MS, Carla M. Sevin, MD, Gurjit K. Khurana Hershey, MD, PhD, Jay K. Kolls, MD, R. Stokes Peebles, MD  Journal of Allergy and Clinical Immunology  Volume 127, Issue 4, Pages e4 (April 2011) DOI: /j.jaci Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 IL-13Rα1 expression on human TH17 cells. CD4+ T cells were polarized to TH1, TH2, TH17, or iTreg cells. A, IL-13Rα1 relative expression normalized to glyceraldehyde-3-phosphate dehydrogenase and compared with that seen in TH0 cells. B and C, Dot plot of IL-13Rα1 surface expression on CD4+CD3+ cells (Fig 1, B) and total CD4+CD3+IL-13Rα1+ cells (Fig 1, C). Data are composed of 5 to 6 replicates compiled from 3 independent experiments. ∗P < .05 compared with TH0 cells (ANOVA). Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 IL-13 increases STAT6 phosphorylation in TH17 cells. Serum-starved TH0 and TH17 cells were stimulated with IL-13 (10 ng/mL) for 1 hour and examined for phospho-STAT6 (p-STAT6) expression by means of flow cytometry. A, STAT6 phosphorylation in CD3+CD4+ cells compared with the isotype control. B, Fold increase of phospho-STAT6+CD3+CD4+ cells compared with 0 ng/mL IL-13 in respective cell lineages. Data are composed of 4 replicates. ∗P < .05 (ANOVA). Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 TGF-β, IL-1β, and IL-23 upregulate IL-13Rα1 expression. Naive T cells were polarized by using combinations of TH17-polarizing cytokines in the presence of anti–IL-4 and anti–IFN-γ. IL-13Rα1 expression levels determined by means of real-time PCR, normalized to glyceraldehyde-3-phosphate dehydrogenase, and compared with TH0 cells are shown. Data are representative of 3 different experiments. n.s., Not significant. ∗P < .05 compared with TH0 cells (ANOVA). Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 IL-13 attenuates TH17 cytokine production. A-C, Naive T cells were polarized to become TH17 cells in the presence of IL-13, and IL-17A, IL-21, and IL-22 levels were measured. D, TH17 cells were polarized in the presence of the isotype control, anti–IL-4, or anti–IL-13 (all 10 μg/mL), and IL-17A levels were measured. Data are from 3 experiments. ∗P < .05 compared with isotype control (t test [Fig 4, A-C] or ANOVA [Fig 4, D]). Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 5 A-C, IL-13 attenuates IL-17A production in human TH17-polarized cells. CD4+ T cells were polarized to become TH0, TH1, TH2, TH17, or iTreg cells after 4 days in the presence of IL-13 (10 ng/mL). Supernatants were examined by means of ELISA for cytokines. Data are composed of 5 to 6 replicates compiled from 3 independent experiments. ∗P < .05 compared with 0 ng/mL IL-13 for respective T-cell lineages (ANOVA). Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig 6 IL-13 attenuates expression of TH17 transcription factors. A, Serum-starved TH17 cells were stimulated with IL-1β and IL-6 for 15 minutes, and phospho-STAT3 (p-STAT3) levels were examined. B-D, Nuclear protein from TH17 cells was examined for RORC2, Runx1, and IRF-4. Densitometry was normalized to total STAT3 (Fig 6, A) or nucleolin (Fig 6, B-D) and then normalized to TH17 cells. ∗P < .05 compared with 0 ng/mL IL-13 (t test). Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Fig 7 IL-13 decreases IL-17A levels within 24 hours of polarization or at restimulation. A, IL-13 was added to TH17 cells at days 0, 1, or 2, and IL-17A levels were measured 4 days after polarization. B, TH17 cells were restimulated with anti-CD3 and anti-CD28 in the presence or absence of IL-13, and IL-17A levels were measured 24 hours later. ∗P < .05 compared with TH17 cells (ANOVA [A] or t test [B]). Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 Isolated cells are CD3+CD4+ T cells
Isolated cells are CD3+CD4+ T cells. Histograms of cultured T cells 4 days after isolation are shown. Cells were gated on live cells that are CD4+ and are shown as CD3+ cells. Histograms are representative of 3 samples for each T-cell lineage. Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

10 IL-4Rα is expressed in human TH1, TH2, TH17, and iTreg cells
IL-4Rα is expressed in human TH1, TH2, TH17, and iTreg cells. Naive human CD4+ T cells were isolated from PBMCs and cultured in polarizing conditions to become naive (TH0), TH1, TH2, TH17, or iTreg cells for 4 days. Cells were lysed, and RNA was extracted. Measurement of relative expression of IL-4Rα was performed by means of real-time PCR. Real-time data were normalized to glyceraldehyde-3-phosphate dehydrogenase, and relative expression is compared with that of naive (TH0) cells. Data are composed of 5 to 6 replicates compiled from 3 independent experiments. ∗P < .05 compared with TH0 cells (ANOVA). Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

11 Naive CD4+ T cells were activated and polarized to TH17 cells presence of IgG isotype control (10 μg/mL) or anti–IL-13 (1-10 μg/mL) for 4 days, and IL-17A production was measured by means of ELISA for cytokine production. Data are composed of 4 to 6 replicates. ∗P < .05 compared with isotype control (ANOVA). Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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