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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070845

Accepted for publication March 17, 2008.

Article

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

Karl R.N. Baumforth*, Anna Birgersdotter{dagger}, Gary M. Reynolds{ddagger}, Wenbin Wei*, Georgia Kapatai*, Joanne R. Flavell*, Emma Kalk*, Karen Piper*, Steve Lee*, Lee Machado*, Kerry Hadley{sect}, Anne Sundblad, Jan Sjoberg, Magnus Bjorkholm, Anna A. Porwit||, Lee-Fah Yap**, Soohwang Teo**, Richard G. Grundy{dagger}{dagger}, Lawrence S. Young*, Ingemar Ernberg{dagger}, Ciaran B.J. Woodman*, and Paul G. Murray*@

From the Cancer Research United Kingdom Institute for Cancer Studies,* and the Liver Research Laboratories,{ddagger} University of Birmingham, Birmingham, United Kingdom; the Histology Department,{sect} Russells Hall Hospital, Dudley, United Kingdom; The Children's Brain Tumor Research Centre,{dagger}{dagger} University of Nottingham, The Medical School, Nottingham, United Kingdom; the Department of Microbiology, Tumor, and Cell Biology,{dagger} Karolinska Institute, Stockholm, Sweden; the Division of Haematology, and Department of Pathology,|| Karolinska University Hospital, Stockholm, Sweden; and the Cancer Research Initiatives Foundation,** Subang Jaya Medical Centre, Selangor, Malaysia

@ To whom correspondence should be addressed. E-mail: p.g.murray{at}bham.ac.uk.


  Abstract

In ~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.






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Copyright © 2008 by the American Society for Investigative Pathology.