Low Herpesvirus Entry Mediator (HVEM) Expression on Dermal Fibroblasts Contributes to a Th2-Dominant Microenvironment in Advanced Cutaneous T-Cell Lymphoma

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Low Herpesvirus Entry Mediator (HVEM) Expression on Dermal Fibroblasts Contributes to a Th2-Dominant Microenvironment in Advanced Cutaneous T-Cell Lymphoma Tomomitsu Miyagaki, Makoto Sugaya, Hiraku Suga, Sohshi Morimura, Hanako Ohmatsu, Hideki Fujita, Yoshihide Asano, Yayoi Tada, Takafumi Kadono, Shinichi Sato Journal of Investigative Dermatology Volume 132, Issue 4, Pages 1280-1289 (April 2012) DOI: 10.1038/jid.2011.470 Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 CXC chemokine ligand (CXCL)9, CXCL10, and CXCL11 expression by dermal fibroblasts co-stimulated with LIGHT (lymphotoxin-like, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed by T lymphocytes) and IFN-γ. (a, b) Normal human dermal fibroblasts were cultured with medium only or with IFN-γ or IL-4 (1, 10, and 100ngml-1) for 24hours. (a) HVEM expression on fibroblasts shown by flow cytometry. (b) Summary of HVEM expression on cultured fibroblasts. (c, d) Dermal fibroblasts were cultured with medium only or with IFN-γ (10ngml-1) or with LIGHT (1, 10, and 100ngml-1) or with their combination for 24hours. (c) Quantitative reverse transcriptase (RT)–PCR was performed to measure CXCL9, CXCL10, and CXCL11 expression relative to glyceraldehyde-3-phosphate dehydrogenase (GAPDH). (d) CXCL9, CXCL10, and CXCL11 levels in the culture supernatants were measured. Data are presented as mean±standard deviation. *P<0.05. Results are representative of three experiments with similar findings. Journal of Investigative Dermatology 2012 132, 1280-1289DOI: (10.1038/jid.2011.470) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 CXC chemokine ligand (CXCL)9, CXCL10, and CXCL11 expression induced by LIGHT (lymphotoxin-like, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed by T lymphocytes) via phosphorylation of inhibitor κBα (IκBα). (a) Human dermal fibroblasts were cultured with IFN-γ (10ngml-1) or LIGHT (100ngml-1) or their combination. IκBα phosphorylation was detected in fibroblasts stimulated with LIGHT, but not with IFN-γ alone. A representative picture of three experiments is shown. (b, c) Human dermal fibroblasts were cultured with medium only or with IFN-γ (10ngml-1) or LIGHT (1, 10, and 100ng/ml-1) or their combination for 16hours after pre-incubation with medium or sc-514 (20 and 50μM). (b) Quantitative reverse transcriptase (RT)–PCR was performed to measure CXCL9, CXCL10, and CXCL11 expression relative to glyceraldehyde-3-phosphate dehydrogenase (GAPDH). (c) CXCL9, CXCL10, and CXCL11 levels in the culture supernatants were measured. Data are presented as mean±standard deviation. *P<0.05. Results are representative of three experiments. Journal of Investigative Dermatology 2012 132, 1280-1289DOI: (10.1038/jid.2011.470) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Chemokine, chemokine receptor, LIGHT (lymphotoxin-like, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed by T lymphocytes), and HVEM expression in lesional skin and dermal fibroblasts of cutaneous T cell lymphoma (CTCL). (a–c) Messenger RNA was extracted from normal skin and lesional skin of CTCL. Quantitative reverse transcriptase (RT)–PCR was performed to measure (a) CXC chemokine ligand (CXCL)9, CXCL10, CXCL11, (b) CXC chemokine receptor (CXCR)3, CC chemokine receptor (CCR4), (c) LIGHT, and HVEM expression relative to glyceraldehyde-3-phosphate dehydrogenase (GAPDH). (d) Human dermal fibroblasts from normal skin and lesional skin of advanced CTCL were cultured in round-bottom six-well plates with medium only. Total RNA was extracted from fibroblasts, and quantitative RT–PCR was performed to measure HVEM expression relative to GAPDH. The measured values from individual patients are plotted by black diamonds. *P<0.05; **P<0.01. Journal of Investigative Dermatology 2012 132, 1280-1289DOI: (10.1038/jid.2011.470) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Correlations among chemokine, chemokine receptor, LIGHT (lymphotoxin-like, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed by T lymphocytes), and HVEM expression levels in lesional skin of cutaneous T cell lymphoma (CTCL). (a) Correlations between HVEM expression and CXC chemokine ligand (CXCL)9 or CXCL10 expression. (b) Inverse correlation between HVEM expression and CC chemokine receptor (CCR)4 expression and correlation between LIGHT expression and CCR4 expression. (c) Inverse correlation between LIGHT expression and HVEM expression. (d) Correlations among CXCL9 expression, CXCL10 expression, and CXCL11 expression. Journal of Investigative Dermatology 2012 132, 1280-1289DOI: (10.1038/jid.2011.470) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Immunohistochemistry of chemokines, herpesvirus entry mediator (HVEM), LIGHT (lymphotoxin-like, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for HVEM, a receptor expressed by T lymphocytes), and phosphorylated IκBα (pIκBα) in cutaneous T cell lymphoma (CTCL) skin and HVEM expression on circulating tumor cells in Sézary syndrome (SS). (a) Staining of normal skin (left; n=5), early CTCL (middle; n=5), and advanced CTCL (right; n=10) for HVEM, LIGHT, CXC chemokine ligand (CXCL)9, CXCL10, CXCL11, and pIκBα. Arrow indicates dermal fibroblasts. Representative pictures are shown. Bar=100μm. (b–d) Cell numbers per high power field ( × 400). Negative cells (-), slightly positive cells (+), and strongly positive cells (++) were counted for (b) CXCL9, CXCL10, CXCL11, (c) HVEM, and (d) pIκBα. (e) A representative flow-cytometry histogram of HVEM using peripheral blood mononuclear cells from patients with SS. The tumor cells express Vβ13.1. (f) Frequencies of HVEM-positive cells in the malignant T cell clone and the benign T cells in peripheral blood of three patients with SS. Journal of Investigative Dermatology 2012 132, 1280-1289DOI: (10.1038/jid.2011.470) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions