The relationships between Epstein-Barr virus latent membrane protein 1 and regulatory T cells in Hodgkin's lymphoma

Neil Andrew Marshall, Dominic J. Culligan, Jane Tighe, Peter W. Johnston, Robert Norman Barker, Mark Adrian Vickers

Research output: Contribution to journalArticle

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Abstract

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/eytotoxic 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.

Original languageEnglish
Pages (from-to)596-604
Number of pages9
JournalExperimental Hematology
Volume35
Issue number4
Early online date28 Mar 2007
DOIs
Publication statusPublished - Apr 2007

Keywords

  • posttransplant lymphoproliferative disease
  • infectious-mononucleosis
  • adoptive immunotherapy
  • malignant-cells
  • EBV
  • protein
  • identification
  • lymphocytes
  • expression
  • epitopes

Cite this

The relationships between Epstein-Barr virus latent membrane protein 1 and regulatory T cells in Hodgkin's lymphoma. / Marshall, Neil Andrew; Culligan, Dominic J.; Tighe, Jane; Johnston, Peter W.; Barker, Robert Norman; Vickers, Mark Adrian.

In: Experimental Hematology, Vol. 35, No. 4, 04.2007, p. 596-604.

Research output: Contribution to journalArticle

Marshall, Neil Andrew ; Culligan, Dominic J. ; Tighe, Jane ; Johnston, Peter W. ; Barker, Robert Norman ; Vickers, Mark Adrian. / The relationships between Epstein-Barr virus latent membrane protein 1 and regulatory T cells in Hodgkin's lymphoma. In: Experimental Hematology. 2007 ; Vol. 35, No. 4. pp. 596-604.
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abstract = "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/eytotoxic 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.",
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TY - JOUR

T1 - The relationships between Epstein-Barr virus latent membrane protein 1 and regulatory T cells in Hodgkin's lymphoma

AU - Marshall, Neil Andrew

AU - Culligan, Dominic J.

AU - Tighe, Jane

AU - Johnston, Peter W.

AU - Barker, Robert Norman

AU - Vickers, Mark Adrian

PY - 2007/4

Y1 - 2007/4

N2 - 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/eytotoxic 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.

AB - 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/eytotoxic 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.

KW - posttransplant lymphoproliferative disease

KW - infectious-mononucleosis

KW - adoptive immunotherapy

KW - malignant-cells

KW - EBV

KW - protein

KW - identification

KW - lymphocytes

KW - expression

KW - epitopes

U2 - 10.1016/J.EXPHEM.2007.01.030

DO - 10.1016/J.EXPHEM.2007.01.030

M3 - Article

VL - 35

SP - 596

EP - 604

JO - Experimental Hematology

JF - Experimental Hematology

SN - 0301-472X

IS - 4

ER -