Research Article: Early T Cell Recognition of B Cells following Epstein-Barr Virus Infection: Identifying Potential Targets for Prophylactic Vaccination

Date Published: April 20, 2016

Publisher: Public Library of Science

Author(s): Jill M. Brooks, Heather M. Long, Rose J. Tierney, Claire Shannon-Lowe, Alison M. Leese, Martin Fitzpatrick, Graham S. Taylor, Alan B. Rickinson, Stephen Gottschalk.


Epstein-Barr virus, a B-lymphotropic herpesvirus, is the cause of infectious mononucleosis, has strong aetiologic links with several malignancies and has been implicated in certain autoimmune diseases. Efforts to develop a prophylactic vaccine to prevent or reduce EBV-associated disease have, to date, focused on the induction of neutralising antibody responses. However, such vaccines might be further improved by inducing T cell responses capable of recognising and killing recently-infected B cells. In that context, EBNA2, EBNA-LP and BHRF1 are the first viral antigens expressed during the initial stage of B cell growth transformation, yet have been poorly characterised as CD8+ T cell targets. Here we describe CD8+ T cell responses against each of these three “first wave” proteins, identifying target epitopes and HLA restricting alleles. While EBNA-LP and BHRF1 each contained one strong CD8 epitope, epitopes within EBNA2 induced immunodominant responses through several less common HLA class I alleles (e.g. B*3801 and B*5501), as well as subdominant responses through common class I alleles (e.g. B7 and C*0304). Importantly, such EBNA2-specific CD8+ T cells recognised B cells within the first day post-infection, prior to CD8+ T cells against well-characterised latent target antigens such as EBNA3B or LMP2, and effectively inhibited outgrowth of EBV-transformed B cell lines. We infer that “first wave” antigens of the growth-transforming infection, especially EBNA2, constitute potential CD8+ T cell immunogens for inclusion in prophylactic EBV vaccine design.

Partial Text

Epstein-Barr virus (EBV), a human γ-herpesvirus with potent B cell growth-transforming ability, is carried by most individuals as an asymptomatic infection yet has a remarkable potential to cause disease. Thus delayed primary infection of the immune-competent host leads in many cases to infectious mononucleosis (IM), where disease symptoms are coincident with an over-active T cell response [1]; while infection of T cell-compromised or T cell-suppressed patients brings a high risk of EBV-driven B-lymphoproliferative disease (LPD). Equally important, the virus is linked to a number of lymphoid and epithelial malignancies that arise as a consequence of longer-term virus carriage [2,3]. Collectively these EBV genome-positive tumours, including endemic Burkitt Lymphoma, many cases of Hodgkin Lymphoma, adult T/NK cell lymphoma, nasopharyngeal carcinoma and a subset of gastric carcinomas, impose a global disease burden of ~200,000 new cancer cases per year [4]. EBV infection is also implicated as a major environmental risk factor for the development of various autoimmune conditions, especially Multiple Sclerosis [5].

An effective prophylactic EBV vaccine should aim to prevent, or at least limit colonisation of the B cell system, the process that is essential for virus persistence and central to the development of most, if not all, EBV-associated disease. An ideal vaccine might induce both neutralising antibodies to reduce levels of infection and T cell responses to target B cells that do become infected. Proteins that are expressed in the very early phase of B cell transformation, including EBNA2, EBNA-LP and BHRF1, constitute potential vaccine immunogens for the induction of CD8+ T cell responses. Here we have (i) determined to what extent natural EBV infection elicits CD8 responses to these “first wave” proteins, including identification of target epitopes/HLA restricting alleles and assessment of relative immunodominance; (ii) assayed the ability of such T cells to recognise B cells expressing these proteins in the very early phase of infection, prior to cell cycle entry; (iii) compared such recognition with that shown by CD8+ T cells against other potential targets of early detection i.e. IE/E lytic antigens, that may be expressed from mRNAs contained within the virion [22–26], and virus structural proteins delivered into B cells upon infection; and (iv) assessed the ability of such effectors to inhibit EBV-induced B cell transformation and LCL outgrowth.




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