TSLP Directly Interacts with Skin-Homing Th2 Cells Highly Expressing its Receptor to Enhance IL-4 Production in Atopic Dermatitis Kazuki Tatsuno, Toshiharu.

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TSLP Directly Interacts with Skin-Homing Th2 Cells Highly Expressing its Receptor to Enhance IL-4 Production in Atopic Dermatitis Kazuki Tatsuno, Toshiharu Fujiyama, Hayato Yamaguchi, Michihiko Waki, Yoshiki Tokura Journal of Investigative Dermatology Volume 135, Issue 12, Pages 3017-3024 (December 2015) DOI: 10.1038/jid.2015.318 Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 High TSLP receptor (TSLPR) expression on circulating CD4+ T cells in AD patients. Blood samples from atopic dermatitis (AD) patients and normal healthy individuals were collected for flow cytometric analysis. (a) Lymphocyte and monocyte fractions were gated for analysis. (b) Representative TSLPR expression on CD4+ T cells in normal and AD patient samples. (c) Frequency (%) of TSLPR-expressing CD4+ T cells in PBMCs of normal (n=7) and AD patient (n=51) samples. *P<0.005. (d) Immunophenotype of TSLPR-expressing cells in AD patient PBMCs. (e) FoxP3 expression of CD4+TSLPR+ T cells. These are data from a representative AD patient expressing high TSLPR expression. Journal of Investigative Dermatology 2015 135, 3017-3024DOI: (10.1038/jid.2015.318) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Frequency of circulating TSLPR+CD4+ T cells correlates with serum CCL17/TARC, IgE levels and eosinophil count. (a) Frequency of circulating CD4+TSLPR+ T cells in atopic dermatitis (AD) patients was compared with clinical parameters. For each analyzed patient, the clinical data use for analysis were ascertained on the same day that flow cytometry was performed, so that all parameters reflect the condition of each patient at one single time point. Spearman’s rank correlation coefficient analysis was used for statistical comparison of frequency of circulating CD4+TSLPR+ T cells with AD clinical markers. ρ>0.5 signify high correlation, and 0.5>P>0.2 show moderate correlation. (b) Comparison of serum CCL17/TARC and circulating TSLPR+CD4+ T cells in in-patient AD individuals (n=4) before and after 2-week treatment. Paired t-test *P<0.05. Journal of Investigative Dermatology 2015 135, 3017-3024DOI: (10.1038/jid.2015.318) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 TCR stimulation and IL-4 enhance TSLPR expression on CD4+ T cells. Purified CD4+ T cells from atopic dermatitis (AD) patients (n=4) were cultured with anti-CD3/CD28 microbeads stimulation with or without rhIL-2 or rhIL-4 for up to 14days. TSLP receptor (TSLPR) expression on CD4+ T cells was assessed on day 4, 6, 9, and 14. (a) Representative analysis data from day 4 and day 14. Frequency (%) and mean fluorescence intensity (MFI) in parentheses. (b) Overall TSLPR expression level (MFI) throughout the culture period. The values represent mean±SE. *P<0.05. (c) Cells were cultured for 14days without TCR stimulation with or without IL-2 or IL-4. Representative flow cytometric data on day 14. (d) TSLPR expression between the three groups on day 14. The values represent mean±SE *P<0.05. Journal of Investigative Dermatology 2015 135, 3017-3024DOI: (10.1038/jid.2015.318) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Thymic stromal lymphopoietin (TSLP) upregulates CCR4 expression and promotes proliferation of IL-4-producing cells. CD4+ T cells from AD patients (n=4) were cultured with rhIL-2, rhIL-4, or rhTSLP. CCR4 expression was evaluated on day 4, 6, 9, and 14. (a) Representative flow cytometric data on samples cultured with TSLP in each evaluated time point. (b) CCR4 expression throughout the culture period. The values represent mean±SE *P<0.05 **P<0.01. CD4+ T cells from AD patients (n=8) were labeled with CFSE and cultured with or without rhIL-4 or rhTSLP. On day 14, intracellular IL-4 staining was performed. (c) Representative flow cytometric data. Squares denote the percentage of proliferating IL-4-producing cells. (d) Proliferation of IL-4-producing cells between samples treated with IL-4 and TSLP was compared. Wilcoxon t-test. *P<0.05. AD, atopic dermatitis. Journal of Investigative Dermatology 2015 135, 3017-3024DOI: (10.1038/jid.2015.318) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Thymic stromal lymphopoietin (TSLP) augments IL-4 production from activated CD4+ T cells. CD4+ T cells from atopic dermatitis (AD) patients and normal individuals were TCR stimulated with or without rhTSLP or anti-TSLPR antibody. Supernatants were collected and IL-4 concentration was measured. Enhancement in IL-4 production by TSLP (%)=(IL-4 production with TCR stimulation and TSLP (with or without anti-TSLPR Ab)—IL-4 production with TCR stimulation alone)/(IL-4 production with TCR stimulation alone) × 100. (a) Comparison between AD (n=23) and normal (n=7) samples. rhTSLP (50ng/ml). Mean±SE *P<0.05. (b) CD4+ T cells from patients (n=5) treated with varying TSLP concentration (0.1ngml−1, 5ngml−1, 25ngml−1, 250ngml−1 rhTSLP). (c) CD4+ T cells from patients (n=5) treated with rhTSLP (5ngml−1) with or without anti-TSLPR antibody (20ugml−1). *P<0.01. Journal of Investigative Dermatology 2015 135, 3017-3024DOI: (10.1038/jid.2015.318) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Thymic stromal lymphopoietin (TSLP) amplify IL-4 receptor (IL-4) receptor, IL-2 receptor (IL-2) receptor and γ-common receptor expression (γ-cR) on CD4+ T cells. Isolated CD4+ T cells from atopic dermatitis (AD) patients (n=5) were cultured with or without IL-2, IL-4 or TSLP, and during the 14-day culture period, expression levels of IL-4R, IL-2R, and γ-cR were analyzed through FACS analysis on day 4, 6, 9, and 14. (a) Representative data at day 14 of culture. Number in parenthesis signifying MFI. (b) The overall expression level of IL-4R, IL-2R, and γ-cR expression level at each evaluation period. The values represent mean±SE *P<0.05 **P<0.01. Journal of Investigative Dermatology 2015 135, 3017-3024DOI: (10.1038/jid.2015.318) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions