The Journal of Experimental Medicine
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Published online 8 May 2000.
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© The Rockefeller University Press, 0022-1007/2000/5/1649/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 10, May 15, 2000 1649-1660

Original Article

Human CD4+ T Lymphocytes Consistently Respond to the Latent Epstein-Barr Virus Nuclear Antigen EBNA1

Christian Münza, Kara L. Bickhama, Marion Subklewea, Ming L. Tsanga, Ann Chahroudia, Michael G. Kurillac, Dan Zhangb, Michael O'Donnellb, and Ralph M. Steinmana
a Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, New York 10021-6399
b Laboratory of DNA Replication and Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10021-6399
c Department of Pathology and Microbiology, University of Virginia, Charlottesville, Virginia 22908

Correspondence to: Ralph M. Steinman, Laboratory of Cellular Physiology and Immunology, The Rockefeller University, 405 Bronk Bldg., 1230 York Ave., New York, NY 10021-6399. Tel:212-327-8106 Fax:212-327-8875 E-mail:steinma{at}rockvax.rockefeller.edu.

The Epstein-Barr virus (EBV)-encoded nuclear antigen EBNA1 is critical for the persistence of the viral episome in replicating EBV-transformed human B cells. Therefore, all EBV-induced tumors express this foreign antigen. However, EBNA1 is invisible to CD8+ cytotoxic T lymphocytes because its Gly/Ala repeat domain prevents proteasome-dependent processing for presentation on major histocompatibility complex (MHC) class I. We now describe that CD4+ T cells from healthy adults are primed to EBNA1. In fact, among latent EBV antigens that stimulate CD4+ T cells, EBNA1 is preferentially recognized. We present evidence that the CD4+ response may provide a protective role, including interferon {gamma} secretion and direct cytolysis after encounter of transformed B lymphocyte cell lines (B-LCLs). Dendritic cells (DCs) process EBNA1 from purified protein and from MHC class II–mismatched, EBNA1-expressing cells including B-LCLs. In contrast, B-LCLs and Burkitt's lymphoma lines likely present EBNA1 after endogenous processing, as their capacity to cross-present from exogenous sources is weak or undetectable. By limiting dilution, there is a tight correlation between the capacity of CD4+ T cell lines to recognize autologous B-LCL–expressing EBNA1 and DCs that have captured EBNA1. Therefore, CD4+ T cells can respond to the EBNA1 protein that is crucial for EBV persistence. We suggest that this immune response is initiated in vivo by DCs that present EBV-infected B cells, and that EBNA1-specific CD4+ T cell immunity be enhanced to prevent and treat EBV-associated malignancies.

Key Words: Epstein-Barr virus, Epstein-Barr virus nuclear antigen 1, CD4+ T cell, cross-presentation, dendritic cells


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