Expression of the Epstein-Barr virus-encoded Epstein-Barr virus nuclear antigen 1 in Hodgkin's Lymphoma cells mediates Up-regulation of CCL20 and the migration of regulatory T cells

K R N Baumforth, Anna Birgersdotter, G M Reynolds, Wenbin Wei, Georgia Kapatai, Joanne Flavell, Emma Kalk, Karen Piper, S P Lee, Lee Machado, Kerry Hadley, Anne Sundblad, Jan Sjoberg, Magnus Bjorkholm, Anna Porwit, Lee-Fah Yap, Soohwang Teo, Richard Grundy, L S Young, Ingemar ErnbergCiaran Woodman, Paul Murray

Research output: Contribution to JournalArticlepeer-review

Abstract

In approximately 50% of patients with Hodgkin's lymphoma (HL), the Epstein-Barr virus (EBV), an oncogenic herpesvirus, is present in tumor cells. After microarray profiling of both HL tumors and cell lines, we found that EBV infection increased the expression of the chemokine CCL20 in both primary Hodgkin and Reed-Sternberg cells and Hodgkin and Reed-Sternberg cell-derived cell lines. Additionally, this up-regulation could be mediated by the EBV nuclear antigen 1 protein. The higher levels of CCL20 in the supernatants of EBV-infected HL cell lines increased the migration of CD4(+) lymphocytes that expressed FOXP3, a marker of regulatory T cells (Tregs), which are specialized CD4(+) T cells that inhibit effector CD4(+) and CD8(+) T cells. In HL, an increased number of Tregs is associated with the loss of EBV-specific immunity. Our results identify a mechanism by which EBV can recruit Tregs to the microenvironment of HL by inducing the expression of CCL20 and, by doing so, prevent immune responses against the virus-infected tumor population. Further investigation of how EBV recruits and modifies Tregs will contribute not only to our understanding of the pathogenesis of virus-associated tumors but also to the development of therapeutic strategies designed to manipulate Treg activity.
Original languageEnglish
Pages (from-to)195-204
JournalThe American Journal of Pathology
Volume173
Issue number1
DOIs
Publication statusPublished - 1 Jul 2008

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