HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Haigh, T. A. Articles by Taylor, G. S. Search for Related Content PubMed PubMed Citation Articles by Haigh, T. A. Articles by Taylor, G. S. Pubmed/NCBI databases Substance via MeSH

EBV Latent Membrane Proteins (LMPs) 1 and 2 as Immunotherapeutic Targets: LMP-Specific CD4⁺ Cytotoxic T Cell Recognition of EBV-Transformed B Cell Lines¹

Tracey A. Haigh^*, Xiaorong Lin, Hui Jia^*, Edwin P. Hui, Anthony T. C. Chan, Alan B. Rickinson^2,* and Graham S. Taylor^*

^* Cancer Research United Kingdom Institute for Cancer Studies, University of Birmingham, Birmingham, United Kingdom; and State Key Laboratory in Oncology in South China, Sir Y. K. Pao Centre for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute, The Chinese University of Hong Kong, Hong Kong, People’s Republic of China

The EBV-latent membrane proteins (LMPs) 1 and 2 are among only three viral proteins expressed in EBV-associated Hodgkin’s lymphoma and nasopharyngeal carcinoma. Since these tumors are HLA class I and class II-positive, the LMPs could serve as both CD8⁺ and CD4⁺ T cell targets. In contrast to CD8 responses, very little is known about CD4 responses to LMPs. In this study, we describe CD4⁺ T cell clones defining four LMP1- and three LMP2-derived peptide epitopes and their restricting alleles. All clones produced Th1-like cytokines in response to peptide and most killed peptide-loaded target cells by perforin-mediated lysis. Although clones to different epitopes showed different functional avidities in peptide titration assays, avidity per se was a poor predictor of the ability to recognize naturally infected B lymphoblastoid cell lines (LCLs) expressing LMPs at physiologic levels. Some epitopes, particularly within LMP1, consistently mediated strong LCL recognition detectable in cytokine release, cytotoxicity, and outgrowth inhibition assays. Using cyclosporin A to selectively block cytokine release, we found that CD4⁺ T cell cytotoxicity is the key effector of LCL outgrowth control. We therefore infer that cytotoxic CD4⁺ T cells to a subset of LMP epitopes could have therapeutic potential against LMP-expressing tumors.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from Cancer Research U.K. and the Hong Kong Cancer Fund.

² Address correspondence and reprint requests to Dr. Alan B. Rickinson, Cancer Research United Kingdom Institute for Cancer Studies, University of Birmingham, Vincent Drive, Edgbaston, Birmingham, B15 2TT, U.K. E-mail address: a.b.rickinson{at}bham.ac.uk

³ Abbreviations used in this paper: PTLD, posttransplant lymphoproliferative disease; EBNA, EBV-encoded nuclear Ag; LCL, lymphoblastoid cell line; HL, Hodgkin’s lymphoma; NPC, nasopharyngeal carcinoma; CSA, cyclosporin A.