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Journal of Virology, September 2001, p. 8649-8659, Vol. 75, No. 18
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.18.8649-8659.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Differential Immunogenicity of Epstein-Barr Virus Latent-Cycle Proteins for Human CD4+ T-Helper 1 Responses

Ann Leen,1 Pauline Meij,2 Irina Redchenko,1 Jaap Middeldorp,2 Elisabeth Bloemena,2 Alan Rickinson,1,* and Neil Blake1

CRC Institute for Cancer Studies and MRC Centre for Immune Regulation, Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom,1 and Department of Pathology, Academic Hospital Vrije Universiteit, Amsterdam, The Netherlands2

Received 5 February 2001/Accepted 5 June 2001

Human CD4+ T-helper 1 cell responses to Epstein-Barr virus (EBV) infection are likely to be important in the maintenance of virus-specific CD8+ memory and/or as antiviral effectors in their own right. The present work has used overlapping peptides as stimulators of gamma interferon release (i) to identify CD4+ epitopes within four EBV latent-cycle proteins, i.e., the nuclear antigens EBNA1 and EBNA3C and the latent membrane proteins LMP1 and LMP2, and (ii) to determine the frequency and magnitude of memory responses to these proteins in healthy virus carriers. Responses to EBNA1 and EBNA3C epitopes were detected in the majority of donors, and in the case of EBNA1, their antigen specificity was confirmed by in vitro reactivation and cloning of CD4+ T cells using protein-loaded dendritic cell stimulators. By contrast, responses to LMP1 and LMP2 epitopes were seen much less frequently. EBV latent-cycle proteins therefore display a marked hierarchy of immunodominance for CD4+ T-helper 1 cells (EBNA1, EBNA3C LMP1, LMP2) which is different from that identified for the same proteins with respect to CD8+-T-cell responses (EBNA3C > EBNA1 > LMP2 LMP1). Furthermore, the range of CD4+ memory T-cell frequencies in peripheral blood of healthy virus carriers was noticeably lower and narrower than the corresponding range of latent antigen-specific CD8+-T-cell frequencies.

* Corresponding author. Mailing address: CRC Institute for Cancer Studies, University of Birmingham, Medical School, Vincent Dr., Edgbaston, Birmingham B15 2TT, United Kingdom. Phone: 44-121-414 4485. Fax: 44-121-414 4486. E-mail: A.B.Rickinson{at}Bham.ac.uk.

Journal of Virology, September 2001, p. 8649-8659, Vol. 75, No. 18
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.18.8649-8659.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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