Cytolytic T lymphocytes from HLA-B8+ donors frequently recognize the Hodgkin's lymphoma associated latent membrane protein 2 of Epstein Barr virus

Ming L Tsang,Christian Münz

doi:10.1186/2042-4280-2-4

Ming L Tsang, Christian Münz

Open Access

https://doi.org/10.1186/2042-4280-2-4

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Journal: Herpesviridae	Publication Date: Jan 1, 2011
Citations: 58	License type: cc-by

Affiliation: Rockefeller University, University of Zurich

Abstract

Epstein Barr virus (EBV) is a lymphotrophic γ-herpesvirus that infects more than 90% of the adult human population. It transforms B cells in vitro and is associated with lymphomas in vivo. In most EBV carriers the emergence of these malignancies, however, is prevented by T cell mediated immune control. Part of this control is mediated by CD8+ T cells, which mainly target a subset of viral nuclear antigens, EBNA3A, B and C, in healthy EBV carriers. In HLA-B8 positive individuals, the dominant CTL response is biased towards recognition of EBNA3A. However, spontaneously arising EBV-associated malignancies, such as Hodgkin's lymphoma and nasopharyngeal carcinoma do not express EBNA3s and instead express latent membrane protein 2 (LMP2) as well as LMP1 and EBNA1. Here we describe the new HLA-B8 restricted, LMP2 derived CD8+ T cell epitope, LMP2345-352. Although the frequency of LMP2345-352 specific CD8+ T cells is usually lower than immunodominant EBNA3A specific CD8+ T cells in fresh blood, the former can be expanded in the majority of HLA-B8+ EBV carriers after 1 week co-culture with peptide pulsed dendritic cells. We demonstrate that LMP2345-352 specific CD8+ T cells secrete IFN-γ and kill both peptide pulsed targets as well as HLA-B8 matched LCL and LMP2 expressing Hodgkin's lymphoma cells. We suggest that cytotoxic CD8+ T cell responses against LMP2 coexist with the immunodominant EBNA3 specific responses in healthy EBV carriers and help to resist EBV associated malignancies.

Highlights

Afterwards, the cultures were assayed for IFN-g secretion in response to the autologous lymphoblastoid cell lines (LCL) or alternatively, autologous Dendritic cells (DC) infected with recombinant vaccinia viruses encoding the latent Epstein Barr virus (EBV) antigens EBNA1, EBNA2, EBNA3B, EBNA3C, LMP1 and latent membrane protein 2 (LMP2) as well as the lytic EBV antigen BMLF1 (Figure 1)
We studied HLA-B8 restricted CD8+ T cell responses directed against this antigen and demonstrate that LMP2 reactivity is present despite the strong EBNA3A specific CD8+ T cell responses that are consistently associated with this HLA
The frequency in whole peripheral blood is usually lower for LMP2 specific than for EBNA3A specific HLA-B8 restricted CD8+ T cells, both reactivities can be expanded to similar levels upon in vitro stimulation with peptide pulsed DCs

Summary

Introduction

The human g-herpesvirus Epstein Barr virus (EBV) establishes a life-long, mostly asymptomatic infection in more than 90% of human adults. It persists in latently infected B cells. Virus infected naïve B cells in tonsils of healthy EBV carriers express all latent antigens, the six nuclear antigens (EBNA1, 2, 3A, 3B, 3C and LP) and the two membrane proteins (LMP1 and 2) [1]. This expression pattern can be found after transformation of B cells in immunosuppressed hosts or in vitro generated lymphoblastoid cell lines (LCL) [2].

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