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.
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.
Baumforth
Karl R N
KR
Cancer Research United Kingdom Institute for Cancer Studies, University of Birmingham, Birmingham, United Kingdom.
Birgersdotter
Anna
A
Reynolds
Gary M
GM
Wei
Wenbin
W
Kapatai
Georgia
G
Flavell
Joanne R
JR
Kalk
Emma
E
Piper
Karen
K
Lee
Steve
S
Machado
Lee
L
Hadley
Kerry
K
Sundblad
Anne
A
Sjoberg
Jan
J
Bjorkholm
Magnus
M
Porwit
Anna A
AA
Yap
Lee-Fah
LF
Teo
Soohwang
S
Grundy
Richard G
RG
Young
Lawrence S
LS
Ernberg
Ingemar
I
Woodman
Ciaran B J
CB
Murray
Paul G
PG
D000328:Adult; D045744:Cell Line, Tumor; D054418:Chemokine CCL20 / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D020031:Epstein-Barr Virus Infections / Q000276:immunology*; D019309:Epstein-Barr Virus Nuclear Antigens / Q000096:biosynthesis* / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D006689:Hodgkin Disease / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D042282:Microdissection; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D016539:Reed-Sternberg Cells; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D019139:Tumor Escape / Q000276:immunology; D015854:Up-Regulation
C108355:CCL20 protein, human; D054418:Chemokine CCL20; D019309:Epstein-Barr Virus Nuclear Antigens; C417029:EBV-encoded nuclear antigen 1