The Journal of Experimental Medicine
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Published online 9 February 2004 doi:10.1084/jem.20031219
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 4, 459-470
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Evidence for the Presentation of Major Histocompatibility Complex Class I–restricted Epstein-Barr Virus Nuclear Antigen 1 Peptides to CD8+ T Lymphocytes

Kui Shin Voo1, Tihui Fu1, Helen Y. Wang1, Judy Tellam3, Helen E. Heslop2, Malcolm K. Brenner2, Cliona M. Rooney2, and Rong-Fu Wang1

1 Department of Immunology, The Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030
2 Department of Pediatrics, The Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030
3 Division of Infectious Diseases and Immunology, Queensland Institute of Medical Research, University of Queensland, Brisbane, Queensland 4006, Australia

Address correspondence to Rong-Fu Wang, Baylor College of Medicine, ALKEK Building, N1120, One Baylor Plaza, Houston, TX 77030. Phone: (713) 798-1244; Fax: (713) 798-1263; email: rongfuw{at}bcm.tmc.edu

The Epstein-Barr virus (EBV)-encoded nuclear antigen 1 (EBNA1) is expressed in all EBV-associated tumors, making it an important target for immunotherapy. However, evidence for major histocompatibility complex (MHC) class I–restricted EBNA1 peptides endogenously presented by EBV-transformed B and tumor cells remains elusive. Here we describe for the first time the identification of an endogenously processed human histocompatibility leukocyte antigen (HLA)-B8–restricted EBNA1 peptide that is recognized by CD8+ T cells. T cell recognition could be inhibited by the treatment of target cells with proteasome inhibitors that block the MHC class I antigen processing pathway, but not by an inhibitor (chloroquine) of MHC class II antigen processing. We also demonstrate that new protein synthesis is required for the generation of the HLA-B8 epitope for T cell recognition, suggesting that defective ribosomal products (DRiPs) are the major source of T cell epitopes. Experiments with protease inhibitors indicate that some serine proteases may participate in the degradation of EBNA1 DRiPs before they are further processed by proteasomes. These findings not only provide the first evidence of the presentation of an MHC class I–restricted EBNA1 epitope to CD8+ T cells, but also offer new insight into the molecular mechanisms involved in the processing and presentation of EBNA1.

Key Words: cancer vaccines • immunotherapy • MHC class I–restricted peptides • antigen presentation • CD8+ T cells

Abbreviations used in this paper: BL, Burkitt's lymphoma; DRiPs, defective ribosomal products; EBNA1, EBV-encoded nuclear antigen 1; E/T, effector to target; GAr, Gly-Ala repeat; GFP, green fluorescent protein; HD, Hodgkin's disease; LCL, EBV-transformed B lymphoblastoid cell line; NPC, nasopharyngeal carcinoma; TRP2, tyrosinase-related protein 2; ZAL, Z-Ile-Glu(OtBu)-Ala-Leucinal.


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