Logo of jexpmedHomeThe Rockefeller University PressEditorsContactInstructions for AuthorsThis issue
J Exp Med. 1992 Jul 1; 176(1): 157–168.
PMCID: PMC2119296

Identification of target antigens for the human cytotoxic T cell response to Epstein-Barr virus (EBV): implications for the immune control of EBV-positive malignancies


Epstein-Barr virus (EBV), a human herpes virus with oncogenic potential, persists in B lymphoid tissues and is controlled by virus- specific cytotoxic T lymphocyte (CTL) surveillance. On reactivation in vitro, these CTLs recognize EBV-transformed lymphoblastoid cell lines (LCLs) in an HLA class I antigen-restricted fashion, but the viral antigens providing target epitopes for such recognition remain largely undefined. Here we have tested EBV-induced polyclonal CTL preparations from 16 virus-immune donors on appropriate fibroblast targets in which the eight EBV latent proteins normally found in LCLs (Epstein-Barr nuclear antigen [EBNA] 1, 2, 3A, 3B, 3C, leader protein [LP], and latent membrane protein [LMP] 1 and 2) have been expressed individually from recombinant vaccinia virus vectors. Most donors gave multicomponent responses with two or more separate reactivities against different viral antigens. Although precise target antigen choice was clearly influenced by the donor's HLA class I type, a subset of latent proteins, namely EBNA 3A, 3B, and 3C, provided the dominant targets on a range of HLA backgrounds; thus, 15 of 16 donors gave CTL responses that contained reactivities to one or more proteins of this subset. Examples of responses to other latent proteins, namely LMP 2 and EBNA 2, were detected through specific HLA determinants, but we did not observe reactivities to EBNA 1, EBNA LP, or LMP 1. The bulk polyclonal CTL response in one donor, and components of that response in others, did not map to any of the known latent proteins, suggesting that other viral target antigens remain to be identified. This work has important implications for CTL control over EBV-positive malignancies where virus gene expression is often limited to specific subsets of latent proteins.

Full Text

The Full Text of this article is available as a PDF (1.1M).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Townsend AR, Rothbard J, Gotch FM, Bahadur G, Wraith D, McMichael AJ. The epitopes of influenza nucleoprotein recognized by cytotoxic T lymphocytes can be defined with short synthetic peptides. Cell. 1986 Mar 28;44(6):959–968. [PubMed]
  • Townsend A, Bodmer H. Antigen recognition by class I-restricted T lymphocytes. Annu Rev Immunol. 1989;7:601–624. [PubMed]
  • Magrath I. The pathogenesis of Burkitt's lymphoma. Adv Cancer Res. 1990;55:133–270. [PubMed]
  • Weiss LM, Movahed LA, Warnke RA, Sklar J. Detection of Epstein-Barr viral genomes in Reed-Sternberg cells of Hodgkin's disease. N Engl J Med. 1989 Feb 23;320(8):502–506. [PubMed]
  • Anagnostopoulos I, Herbst H, Niedobitek G, Stein H. Demonstration of monoclonal EBV genomes in Hodgkin's disease and Ki-1-positive anaplastic large cell lymphoma by combined Southern blot and in situ hybridization. Blood. 1989 Aug 1;74(2):810–816. [PubMed]
  • Dambaugh T, Hennessy K, Chamnankit L, Kieff E. U2 region of Epstein-Barr virus DNA may encode Epstein-Barr nuclear antigen 2. Proc Natl Acad Sci U S A. 1984 Dec;81(23):7632–7636. [PMC free article] [PubMed]
  • Sample J, Young L, Martin B, Chatman T, Kieff E, Rickinson A, Kieff E. Epstein-Barr virus types 1 and 2 differ in their EBNA-3A, EBNA-3B, and EBNA-3C genes. J Virol. 1990 Sep;64(9):4084–4092. [PMC free article] [PubMed]
  • Moss DJ, Misko IS, Burrows SR, Burman K, McCarthy R, Sculley TB. Cytotoxic T-cell clones discriminate between A- and B-type Epstein-Barr virus transformants. Nature. 1988 Feb 25;331(6158):719–721. [PubMed]
  • Murray RJ, Kurilla MG, Griffin HM, Brooks JM, Mackett M, Arrand JR, Rowe M, Burrows SR, Moss DJ, Kieff E, et al. Human cytotoxic T-cell responses against Epstein-Barr virus nuclear antigens demonstrated by using recombinant vaccinia viruses. Proc Natl Acad Sci U S A. 1990 Apr;87(8):2906–2910. [PMC free article] [PubMed]
  • Wallace LE, Young LS, Rowe M, Rowe D, Rickinson AB. Epstein-Barr virus-specific T-cell recognition of B-cell transformants expressing different EBNA 2 antigens. Int J Cancer. 1987 Mar 15;39(3):373–379. [PubMed]
  • Baer R, Bankier AT, Biggin MD, Deininger PL, Farrell PJ, Gibson TJ, Hatfull G, Hudson GS, Satchwell SC, Séguin C, et al. DNA sequence and expression of the B95-8 Epstein-Barr virus genome. Nature. 1984 Jul 19;310(5974):207–211. [PubMed]
  • Sample J, Liebowitz D, Kieff E. Two related Epstein-Barr virus membrane proteins are encoded by separate genes. J Virol. 1989 Feb;63(2):933–937. [PMC free article] [PubMed]
  • Coupar BE, Andrew ME, Both GW, Boyle DB. Temporal regulation of influenza hemagglutinin expression in vaccinia virus recombinants and effects on the immune response. Eur J Immunol. 1986 Dec;16(12):1479–1487. [PubMed]
  • Khanna R, Jacob CA, Burrows SR, Kurilla MG, Kieff E, Misko IS, Sculley TB, Moss DJ. Expression of Epstein-Barr virus nuclear antigens in anti-IgM-stimulated B cells following recombinant vaccinia infection and their recognition by human cytotoxic T cells. Immunology. 1991 Nov;74(3):504–510. [PMC free article] [PubMed]
  • Liebowitz D, Kopan R, Fuchs E, Sample J, Kieff E. An Epstein-Barr virus transforming protein associates with vimentin in lymphocytes. Mol Cell Biol. 1987 Jul;7(7):2299–2308. [PMC free article] [PubMed]
  • Fuerst TR, Earl PL, Moss B. Use of a hybrid vaccinia virus-T7 RNA polymerase system for expression of target genes. Mol Cell Biol. 1987 Jul;7(7):2538–2544. [PMC free article] [PubMed]
  • Rowe M, Evans HS, Young LS, Hennessy K, Kieff E, Rickinson AB. Monoclonal antibodies to the latent membrane protein of Epstein-Barr virus reveal heterogeneity of the protein and inducible expression in virus-transformed cells. J Gen Virol. 1987 Jun;68(Pt 6):1575–1586. [PubMed]
  • Young L, Alfieri C, Hennessy K, Evans H, O'Hara C, Anderson KC, Ritz J, Shapiro RS, Rickinson A, Kieff E, et al. Expression of Epstein-Barr virus transformation-associated genes in tissues of patients with EBV lymphoproliferative disease. N Engl J Med. 1989 Oct 19;321(16):1080–1085. [PubMed]
  • Rowe M, Young LS, Cadwallader K, Petti L, Kieff E, Rickinson AB. Distinction between Epstein-Barr virus type A (EBNA 2A) and type B (EBNA 2B) isolates extends to the EBNA 3 family of nuclear proteins. J Virol. 1989 Mar;63(3):1031–1039. [PMC free article] [PubMed]
  • Yao QY, Rowe M, Martin B, Young LS, Rickinson AB. The Epstein-Barr virus carrier state: dominance of a single growth-transforming isolate in the blood and in the oropharynx of healthy virus carriers. J Gen Virol. 1991 Jul;72(Pt 7):1579–1590. [PubMed]
  • Longnecker R, Kieff E. A second Epstein-Barr virus membrane protein (LMP2) is expressed in latent infection and colocalizes with LMP1. J Virol. 1990 May;64(5):2319–2326. [PMC free article] [PubMed]
  • Wallace LE, Rowe M, Gaston JS, Rickinson AB, Epstein MA. Cytotoxic T cell recognition of Epstein-Barr virus-infected B cells. III. Establishment of HLA-restricted cytotoxic T cell lines using interleukin 2. Eur J Immunol. 1982 Dec;12(12):1012–1018. [PubMed]
  • Wallace LE, Houghton MA, Rickinson AB, Epstein MA, Bradley BA. Allospecific T cell recognition of HLA-A2 antigens: evidence for group-specific and subgroup-specific epitopes. Immunogenetics. 1985;21(3):201–214. [PubMed]
  • Sample J, Hummel M, Braun D, Birkenbach M, Kieff E. Nucleotide sequences of mRNAs encoding Epstein-Barr virus nuclear proteins: a probable transcriptional initiation site. Proc Natl Acad Sci U S A. 1986 Jul;83(14):5096–5100. [PMC free article] [PubMed]
  • López de Castro JA. HLA-B27 and HLA-A2 subtypes: structure, evolution and function. Immunol Today. 1989 Jul;10(7):239–246. [PubMed]
  • Burrows SR, Sculley TB, Misko IS, Schmidt C, Moss DJ. An Epstein-Barr virus-specific cytotoxic T cell epitope in EBV nuclear antigen 3 (EBNA 3). J Exp Med. 1990 Jan 1;171(1):345–349. [PMC free article] [PubMed]
  • Burrows SR, Misko IS, Sculley TB, Schmidt C, Moss DJ. An Epstein-Barr virus-specific cytotoxic T-cell epitope present on A- and B-type transformants. J Virol. 1990 Aug;64(8):3974–3976. [PMC free article] [PubMed]
  • Khanna R, Burrows SR, Kurilla MG, Jacob CA, Misko IS, Sculley TB, Kieff E, Moss DJ. Localization of Epstein-Barr virus cytotoxic T cell epitopes using recombinant vaccinia: implications for vaccine development. J Exp Med. 1992 Jul 1;176(1):169–176. [PMC free article] [PubMed]
  • Wang F, Petti L, Braun D, Seung S, Kieff E. A bicistronic Epstein-Barr virus mRNA encodes two nuclear proteins in latently infected, growth-transformed lymphocytes. J Virol. 1987 Apr;61(4):945–954. [PMC free article] [PubMed]
  • Murray RJ, Wang D, Young LS, Wang F, Rowe M, Kieff E, Rickinson AB. Epstein-Barr virus-specific cytotoxic T-cell recognition of transfectants expressing the virus-coded latent membrane protein LMP. J Virol. 1988 Oct;62(10):3747–3755. [PMC free article] [PubMed]
  • Murray RJ, Brooks JM, Rickinson AB, Rowe M. Cross-recognition of a mouse H-2-peptide complex by human HLA-restricted cytotoxic T cells. Eur J Immunol. 1990 Mar;20(3):659–664. [PubMed]
  • Wang F, Gregory C, Sample C, Rowe M, Liebowitz D, Murray R, Rickinson A, Kieff E. Epstein-Barr virus latent membrane protein (LMP1) and nuclear proteins 2 and 3C are effectors of phenotypic changes in B lymphocytes: EBNA-2 and LMP1 cooperatively induce CD23. J Virol. 1990 May;64(5):2309–2318. [PMC free article] [PubMed]
  • Yates J, Warren N, Reisman D, Sugden B. A cis-acting element from the Epstein-Barr viral genome that permits stable replication of recombinant plasmids in latently infected cells. Proc Natl Acad Sci U S A. 1984 Jun;81(12):3806–3810. [PMC free article] [PubMed]
  • Rowe M, Rowe DT, Gregory CD, Young LS, Farrell PJ, Rupani H, Rickinson AB. Differences in B cell growth phenotype reflect novel patterns of Epstein-Barr virus latent gene expression in Burkitt's lymphoma cells. EMBO J. 1987 Sep;6(9):2743–2751. [PMC free article] [PubMed]
  • Young LS, Dawson CW, Clark D, Rupani H, Busson P, Tursz T, Johnson A, Rickinson AB. Epstein-Barr virus gene expression in nasopharyngeal carcinoma. J Gen Virol. 1988 May;69(Pt 5):1051–1065. [PubMed]
  • Fåhraeus R, Fu HL, Ernberg I, Finke J, Rowe M, Klein G, Falk K, Nilsson E, Yadav M, Busson P, et al. Expression of Epstein-Barr virus-encoded proteins in nasopharyngeal carcinoma. Int J Cancer. 1988 Sep 15;42(3):329–338. [PubMed]
  • Gotch F, McMichael A, Smith G, Moss B. Identification of viral molecules recognized by influenza-specific human cytotoxic T lymphocytes. J Exp Med. 1987 Feb 1;165(2):408–416. [PMC free article] [PubMed]
  • Gotch F, Rothbard J, Howland K, Townsend A, McMichael A. Cytotoxic T lymphocytes recognize a fragment of influenza virus matrix protein in association with HLA-A2. Nature. 326(6116):881–882. [PubMed]
  • McMichael AJ, Gotch FM, Rothbard J. HLA B37 determines an influenza A virus nucleoprotein epitope recognized by cytotoxic T lymphocytes. J Exp Med. 1986 Nov 1;164(5):1397–1406. [PMC free article] [PubMed]
  • Walker BD, Plata F. Cytotoxic T lymphocytes against HIV. AIDS. 1990 Mar;4(3):177–184. [PubMed]
  • Nixon DF, McMichael AJ. Cytotoxic T-cell recognition of HIV proteins and peptides. AIDS. 1991 Sep;5(9):1049–1059. [PubMed]
  • Thomas JA, Hotchin NA, Allday MJ, Amlot P, Rose M, Yacoub M, Crawford DH. Immunohistology of Epstein-Barr virus-associated antigens in B cell disorders from immunocompromised individuals. Transplantation. 1990 May;49(5):944–953. [PubMed]
  • Starzl TE, Nalesnik MA, Porter KA, Ho M, Iwatsuki S, Griffith BP, Rosenthal JT, Hakala TR, Shaw BW, Jr, Hardesty RL, et al. Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy. Lancet. 1984 Mar 17;1(8377):583–587. [PMC free article] [PubMed]
  • Rooney CM, Rowe M, Wallace LE, Rickinson AB. Epstein-Barr virus-positive Burkitt's lymphoma cells not recognized by virus-specific T-cell surveillance. Nature. 1985 Oct 17;317(6038):629–631. [PubMed]
  • Brooks L, Yao QY, Rickinson AB, Young LS. Epstein-Barr virus latent gene transcription in nasopharyngeal carcinoma cells: coexpression of EBNA1, LMP1, and LMP2 transcripts. J Virol. 1992 May;66(5):2689–2697. [PMC free article] [PubMed]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press


Save items

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • PubMed
    PubMed citations for these articles
  • Taxonomy
    Taxonomy records associated with the current articles through taxonomic information on related molecular database records (Nucleotide, Protein, Gene, SNP, Structure).
  • Taxonomy Tree
    Taxonomy Tree

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...