The Journal of Experimental Medicine
BioSymposia
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Published 17 May 2004. doi:10.1084/jem.20040121
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 10, 1409-1420
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CD8 T Cell Recognition of Endogenously Expressed Epstein-Barr Virus Nuclear Antigen 1

Steven P. Lee1, Jill M. Brooks1, Hatim Al-Jarrah2, Wendy A. Thomas1, Tracey A. Haigh1, Graham S. Taylor1, Sibille Humme3, Aloys Schepers3, Wolfgang Hammerschmidt3, John L. Yates4, Alan B. Rickinson1, and Neil W. Blake2

1 Institute for Cancer Studies, The University of Birmingham, Birmingham B15 2TT, UK
2 Department of Medical Microbiology, University of Liverpool, Liverpool L69 36A, UK
3 Department of Gene Vectors, GSF-National Research Centre for Environment and Health, 81377 Munich, Germany
4 Department of Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263

Address correspondence to Steven P. Lee, Institute for Cancer Studies, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 2TT, UK. Phone: 44-121-414-2803; Fax: 44-121-414-4486; email: s.p.lee{at}bham.ac.uk

The Epstein-Barr virus (EBV) nuclear antigen (EBNA)1 contains a glycine-alanine repeat (GAr) domain that appears to protect the antigen from proteasomal breakdown and, as measured in cytotoxicity assays, from major histocompatibility complex (MHC) class I–restricted presentation to CD8+ T cells. This led to the concept of EBNA1 as an immunologically silent protein that although unique in being expressed in all EBV malignancies, could not be exploited as a CD8 target. Here, using CD8+ T cell clones to native EBNA1 epitopes upstream and downstream of the GAr domain and assaying recognition by interferon {gamma} release, we show that the EBNA1 naturally expressed in EBV-transformed lymphoblastoid cell lines (LCLs) is in fact presented to CD8+ T cells via a proteasome/peptide transporter–dependent pathway. Furthermore, LCL recognition by such CD8+ T cells, although slightly lower than seen with paired lines expressing a GAr-deleted EBNA1 protein, leads to strong and specific inhibition of LCL outgrowth in vitro. Endogenously expressed EBNA1 is therefore accessible to the MHC class I pathway despite GAr-mediated stabilization of the mature protein. We infer that EBNA1-specific CD8+ T cells do play a role in control of EBV infection in vivo and might be exploitable in the control of EBV+ malignancies.

Key Words: Epstein-Barr virus • cytotoxic T lymphocytes • antigen presentation • EBNA1

S.P. Lee and J.M. Brooks contributed equally to this work.

Abbreviations used in this paper: BL, Burkitt lymphoma; DriPs, defective ribosomal products; EBNA, EBV nuclear antigen; GAr, glycine-alanine repeat; LCL, lymphoblastoid cell line; TAP, transporter associated with antigen processing.


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