The relationships between Epstein-Barr virus latent membrane protein 1 and regulatory T cells in Hodgkin's lymphoma.
OBJECTIVE
Epstein-Barr virus (EBV) encoded latent membrane protein 1 (LMP1) is expressed by the malignant cells of about 30% of cases of Hodgkin's lymphoma (HL) and is therefore a potential target for immune attack. Given the predominantly immunosuppressive nature of HL infiltrating lymphocytes (HLILs) and the ability of LMP1 to stimulate regulatory T (Treg) responses in healthy donors, we hypothesized that LMP1 was important in the generation of Treg responses in HL.


METHODS
We compared T helper (Th) 1, Th2, and Treg responses to LMP1 by peripheral blood mononuclear cells (PBMCs) and HLILs from EBV-positive and -negative HL patients. The number of Treg cells in patients' PBMCs and HLILs was determined by flow cytometry ex vivo. Proliferation ((3)H-thymidine incorporation) and cytokine (interleukin [IL]-10, IL-4 and gamma-interferon) secretion by LMP1-stimulated PBMCs and HLILs was also measured.


RESULTS
Ex vivo EBV-positive HL patients had increased numbers of IL-10-secreting/cytotoxic T-lymphocyte-associated antigen-4-expressing cells compared with EBV-negative HL patients. PBMC/HLIL responses to LMP1 from most patients were characterized by IL-10 secretion, although isolated HL patients mounted Th1-like responses. Several responses to LMP1 peptides were made by HLILs, which were otherwise unresponsive to control stimuli.


CONCLUSIONS
These results suggest that LMP1 epitopes can induce HLIL Treg cells. However, there was no clear evidence of a greater bias toward regulation in EBV-positive HL cases over EBV-negative cases, and thus there are likely to be other mechanisms of Treg cell induction in EBV-negative HL patients. Manipulating the balance of T-helper response to LMP1 might be exploited in immunotherapy of these lymphomas.
Marshall
Neil A
NA
Department of Medicine and Therapeutics, Insitute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK. marshall@abdn.ac.uk
Culligan
Dominic J
DJ
Tighe
Jane
J
Johnston
Peter W
PW
Barker
Robert N
RN
Vickers
Mark A
MA
D000328:Adult; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D005260:Female; D004854:Herpesvirus 4, Human / Q000302:isolation & purification; D006689:Hodgkin Disease / Q000276:immunology / Q000503:physiopathology* / Q000628:therapy / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000502:physiology*
D016207:Cytokines; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins