Early T Cell Recognition of B Cells following Epstein-Barr Virus Infection: Identifying Potential Targets for Prophylactic Vaccination.
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.
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
Jill M
JM
Brooks
Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.
Heather M
HM
Long
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
Rose J
RJ
Tierney
Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.
Claire
C
Shannon-Lowe
Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.
Alison M
AM
Leese
Biomolecular Mass Spectrometry and Proteomics Group, Utrecht University, Utrecht, The Netherlands.
Martin
M
Fitzpatrick
Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.
Graham S
GS
Taylor
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.|Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.
Alan B
AB
Rickinson
D000956:Antigens, Viral / Q000276:immunology*; D001402:B-Lymphocytes / Q000821:virology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D058501:Enzyme-Linked Immunospot Assay; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D020031:Epstein-Barr Virus Infections / Q000276:immunology*; D006801:Humans; D015151:Immunoblotting; D008213:Lymphocyte Activation / Q000276:immunology*; D014765:Viral Vaccines / Q000276:immunology
D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte; D014765:Viral Vaccines