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Published 17 May 2004. doi:10.1084/jem.20040191
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 10, 1421-1431
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Endogenous Presentation of CD8+ T Cell Epitopes from Epstein-Barr Virus–encoded Nuclear Antigen 1

Judy Tellama,b, Geoff Connollya,b, Katherine J. Greena,b, John J. Milesa,b, Denis J. Mossa,b, Scott R. Burrowsa,b, and Rajiv Khannaa,b

a Tumour Immunology Laboratory, Division of Infectious Diseases and Immunology, Clive Berghofer Cancer Research Centre, Queensland Institute of Medical Research, Brisbane (Qld) 4006, Australia
b Department of Molecular and Cellular Pathology, University of Queensland, Brisbane (Qld) 4006, Australia

Address correspondence to Rajiv Khanna, EBV Unit, Tumour Immunology Laboratory, Division of Infectious Diseases and Immunology, Queensland Institute of Medical Research, 300 Herston Road, Brisbane (Qld) 4006, Australia. Phone: 61-7-33620385; Fax: 61-7-38453510; email: rajivK{at}qimr.edu.au; or Scott R. Burrows, EBV Unit, Tumour Immunology Laboratory, Division of Infectious Diseases and Immunology, Queensland Institute of Medical Research, 300 Herston Road, Brisbane (Qld) 4006, Australia. Phone: 61-7-38453793; Fax: 61-7-38453510; email: scottB{at}qimr.edu.au

Epstein-Barr virus (EBV)–encoded nuclear antigen (EBNA)1 is thought to escape cytotoxic T lymphocyte (CTL) recognition through either self-inhibition of synthesis or by blockade of proteasomal degradation by the glycine-alanine repeat (GAr) domain. Here we show that EBNA1 has a remarkably varied cell type–dependent stability. However, these different degradation rates do not correspond to the level of major histocompatibility complex class I–restricted presentation of EBNA1 epitopes. In spite of the highly stable expression of EBNA1 in B cells, CTL epitopes derived from this protein are efficiently processed and presented to CD8+ T cells. Furthermore, we show that EBV-infected B cells can readily activate EBNA1-specific memory T cell responses from healthy virus carriers. Functional assays revealed that processing of these EBNA1 epitopes is proteasome and transporter associated with antigen processing dependent. We also show that the endogenous presentation of these epitopes is dependent on the newly synthesized protein rather than the long-lived stable EBNA1. Based on these observations, we propose that defective ribosomal products, not the full-length antigen, are the primary source of endogenously processed CD8+ T cell epitopes from EBNA1.

Key Words: EBNA1 • CD8+ T cell • antigen processing • DRiPs • proteasome

S.R. Burrows and R. Khanna contributed equally to this work.

Abbreviations used in this paper: BFA, brefeldin A; DRiPs, defective ribosomal products; EBNA, EBV-encoded nuclear antigen; GAr, glycine-alanine repeat; GFP, green fluorescent protein; HA, hemagglutinin; LCL, lymphoblastoid cell line; LMP1, latent membrane protein 1; TAP, transporter associated with antigen processing; Ub, ubiquitin.


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