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Journal of Virology, November 2003, p. 12088-12104, Vol. 77, No. 22
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.22.12088-12104.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Cytolytic CD4+-T-Cell Clones Reactive to EBNA1 Inhibit Epstein-Barr Virus-Induced B-Cell Proliferation{dagger}

Sarah Nikiforow,1 Kim Bottomly,1 George Miller,2* and Christian Münz3

Departments of Immunobiology,1 Pediatrics, Epidemiology & Public Health, and Molecular Biophysics & Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520,2 Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, New York 10021-63993

Received 15 May 2003/ Accepted 12 August 2003

In the absence of immune surveillance, Epstein-Barr virus (EBV)-infected B cells generate neoplasms in vivo and transformed cell lines in vitro. In an in vitro system which modeled the first steps of in vivo immune control over posttransplant lymphoproliferative disease and lymphomas, our investigators previously demonstrated that memory CD4+ T cells reactive to EBV were necessary and sufficient to prevent proliferation of B cells newly infected by EBV (S. Nikiforow et al., J. Virol. 75:3740-3752, 2001). Here, we show that three CD4+-T-cell clones reactive to the latent EBV antigen EBNA1 also prevent the proliferation of newly infected B cells from major histocompatibility complex (MHC) class II-matched donors, a crucial first step in the transformation process. EBNA1-reactive T-cell clones recognized B cells as early as 4 days after EBV infection through an HLA-DR-restricted interaction. They secreted Th1-type and Th2-type cytokines and lysed EBV-transformed established lymphoblastoid cell lines via a Fas/Fas ligand-dependent mechanism. Once specifically activated, they also caused bystander regression and bystander killing of non-MHC-matched EBV-infected B cells. Since EBNA1 is recognized by CD4+ T cells from nearly all EBV-seropositive individuals and evades detection by CD8+ T cells, EBNA1-reactive CD4+ T cells may control de novo expansion of B cells following EBV infection in vivo. Thus, EBNA1-reactive CD4+-T-cell clones may find use as adoptive immunotherapy against EBV-related lymphoproliferative disease and many other EBV-associated tumors.

* Corresponding author. Mailing address: Department of Pediatrics, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06520. Phone: (203) 785-4758. Fax: (203) 785-6961. E-mail: george.miller{at}yale.edu.

{dagger} We dedicate the manuscript to Charles A. Janeway, Jr.

Journal of Virology, November 2003, p. 12088-12104, Vol. 77, No. 22
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.22.12088-12104.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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