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. 1997 Oct;71(10):7429–7435. doi: 10.1128/jvi.71.10.7429-7435.1997

Hierarchy of Epstein-Barr virus-specific cytotoxic T-cell responses in individuals carrying different subtypes of an HLA allele: implications for epitope-based antiviral vaccines.

R Khanna 1, S R Burrows 1, A Neisig 1, J Neefjes 1, D J Moss 1, S L Silins 1
PMCID: PMC192088  PMID: 9311821

Abstract

Major histocompatibility complex class I-restricted Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes (CTLs) in healthy virus carriers constitute a primary effector arm of the immune system in controlling the proliferation of virus-infected B cells in vivo. These CTLs generally recognize target epitopes included within the latent antigens of the virus. For example, CTLs from HLA B44+ healthy virus carriers often recognize peptide EENLLDFVRF [corrected] from EBV nuclear antigen 6. However, the strength of this response directly correlates with the HLA B44 subtype expressed by the individual donor. Indeed, HLA B*4405+ virus carriers consistently show a very high frequency of CTL precursors for the EENLLDFVRF [corrected] epitope, while a much weaker response is seen in HLA B*4403+ and HLA B*4402+ individuals. This disparity is not due to an intrinsic difference in the CTLs generated by individuals carrying different subtypes of HLA B44. In fact, virus-specific CTLs recognize EENLLDFVRF [corrected] peptide-sensitized HLA B*4405+ target cells more efficiently than B*4402+ or B*4403+ target cells irrespective of the HLA B44 subtype expressed by the donors from whom these effectors were isolated. This effect is evident whether the CTL epitope is endogenously processed or exogenously presented. In addition, a comparison of the intracellular transport kinetics of different B44 subtypes revealed that the B*4405 allele is rapidly assembled and arrives in the trans-Golgi compartment at a faster rate than B*4402 or B*4403. Based on these results, we propose that HLA class I alleles that are capable of binding peptides more efficiently from the intracellular pool, and are rapidly assembled and transported, may confer a protective advantage against viral infection.

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Selected References

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  1. Braciale T. J., Braciale V. L. Antigen presentation: structural themes and functional variations. Immunol Today. 1991 Apr;12(4):124–129. doi: 10.1016/0167-5699(91)90096-C. [DOI] [PubMed] [Google Scholar]
  2. Burrows S. R., Gardner J., Khanna R., Steward T., Moss D. J., Rodda S., Suhrbier A. Five new cytotoxic T cell epitopes identified within Epstein-Barr virus nuclear antigen 3. J Gen Virol. 1994 Sep;75(Pt 9):2489–2493. doi: 10.1099/0022-1317-75-9-2489. [DOI] [PubMed] [Google Scholar]
  3. Burrows S. R., Misko I. S., Sculley T. B., Schmidt C., Moss D. J. An Epstein-Barr virus-specific cytotoxic T-cell epitope present on A- and B-type transformants. J Virol. 1990 Aug;64(8):3974–3976. doi: 10.1128/jvi.64.8.3974-3976.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Burrows S. R., Rodda S. J., Suhrbier A., Geysen H. M., Moss D. J. The specificity of recognition of a cytotoxic T lymphocyte epitope. Eur J Immunol. 1992 Jan;22(1):191–195. doi: 10.1002/eji.1830220128. [DOI] [PubMed] [Google Scholar]
  5. Chen W., Khilko S., Fecondo J., Margulies D. H., McCluskey J. Determinant selection of major histocompatibility complex class I-restricted antigenic peptides is explained by class I-peptide affinity and is strongly influenced by nondominant anchor residues. J Exp Med. 1994 Oct 1;180(4):1471–1483. doi: 10.1084/jem.180.4.1471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Daly K., Nguyen P., Woodland D. L., Blackman M. A. Immunodominance of major histocompatibility complex class I-restricted influenza virus epitopes can be influenced by the T-cell receptor repertoire. J Virol. 1995 Dec;69(12):7416–7422. doi: 10.1128/jvi.69.12.7416-7422.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fazekas de St Groth The evaluation of limiting dilution assays. J Immunol Methods. 1982 Mar 12;49(2):R11–R23. doi: 10.1016/0022-1759(82)90269-1. [DOI] [PubMed] [Google Scholar]
  8. Feltkamp M. C., Smits H. L., Vierboom M. P., Minnaar R. P., de Jongh B. M., Drijfhout J. W., ter Schegget J., Melief C. J., Kast W. M. Vaccination with cytotoxic T lymphocyte epitope-containing peptide protects against a tumor induced by human papillomavirus type 16-transformed cells. Eur J Immunol. 1993 Sep;23(9):2242–2249. doi: 10.1002/eji.1830230929. [DOI] [PubMed] [Google Scholar]
  9. Fleischhauer K., Avila D., Vilbois F., Traversari C., Bordignon C., Wallny H. J. Characterization of natural peptide ligands for HLA-B*4402 and -B*4403: implications for peptide involvement in allorecognition of a single amino acid change in the HLA-B44 heavy chain. Tissue Antigens. 1994 Nov;44(5):311–317. doi: 10.1111/j.1399-0039.1994.tb02401.x. [DOI] [PubMed] [Google Scholar]
  10. Jameson S. C., Bevan M. J. Dissection of major histocompatibility complex (MHC) and T cell receptor contact residues in a Kb-restricted ovalbumin peptide and an assessment of the predictive power of MHC-binding motifs. Eur J Immunol. 1992 Oct;22(10):2663–2667. doi: 10.1002/eji.1830221028. [DOI] [PubMed] [Google Scholar]
  11. Kast W. M., Brandt R. M., Sidney J., Drijfhout J. W., Kubo R. T., Grey H. M., Melief C. J., Sette A. Role of HLA-A motifs in identification of potential CTL epitopes in human papillomavirus type 16 E6 and E7 proteins. J Immunol. 1994 Apr 15;152(8):3904–3912. [PubMed] [Google Scholar]
  12. Khanna R., Burrows S. R., Kurilla M. G., Jacob C. A., Misko I. S., Sculley T. B., Kieff E., Moss D. J. 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. doi: 10.1084/jem.176.1.169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Khanna R., Burrows S. R., Moss D. J. Immune regulation in Epstein-Barr virus-associated diseases. Microbiol Rev. 1995 Sep;59(3):387–405. doi: 10.1128/mr.59.3.387-405.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Khanna R., Jacob C. A., Burrows S. R., Kurilla M. G., Kieff E., Misko I. S., Sculley T. B., Moss D. J. 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] [Google Scholar]
  15. Khanna R., Jacob C. A., Burrows S. R., Moss D. J. Presentation of endogenous viral peptide epitopes by anti-CD40 stimulated human B cells following recombinant vaccinia infection. J Immunol Methods. 1993 Aug 26;164(1):41–49. doi: 10.1016/0022-1759(93)90274-b. [DOI] [PubMed] [Google Scholar]
  16. Lipford G. B., Hoffman M., Wagner H., Heeg K. Primary in vivo responses to ovalbumin. Probing the predictive value of the Kb binding motif. J Immunol. 1993 Feb 15;150(4):1212–1222. [PubMed] [Google Scholar]
  17. Mamula M. J. The inability to process a self-peptide allows autoreactive T cells to escape tolerance. J Exp Med. 1993 Feb 1;177(2):567–571. doi: 10.1084/jem.177.2.567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Moss D. J., Burrows S. R., Baxter G. D., Lavin M. F. T cell-T cell killing is induced by specific epitopes: evidence for an apoptotic mechanism. J Exp Med. 1991 Mar 1;173(3):681–686. doi: 10.1084/jem.173.3.681. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Moss D. J., Misko I. S., Burrows S. R., Burman K., McCarthy R., Sculley T. B. Cytotoxic T-cell clones discriminate between A- and B-type Epstein-Barr virus transformants. Nature. 1988 Feb 25;331(6158):719–721. doi: 10.1038/331719a0. [DOI] [PubMed] [Google Scholar]
  20. Murray R. J., Kurilla M. G., Brooks J. M., Thomas W. A., Rowe M., Kieff E., Rickinson A. B. 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. J Exp Med. 1992 Jul 1;176(1):157–168. doi: 10.1084/jem.176.1.157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Neefjes J. J., Breur-Vriesendorp B. S., van Seventer G. A., Iványi P., Ploegh H. L. An improved biochemical method for the analysis of HLA-class I antigens. Definition of new HLA-class I subtypes. Hum Immunol. 1986 Jun;16(2):169–181. doi: 10.1016/0198-8859(86)90046-7. [DOI] [PubMed] [Google Scholar]
  22. Neefjes J. J., Momburg F., Hämmerling G. J. Selective and ATP-dependent translocation of peptides by the MHC-encoded transporter. Science. 1993 Aug 6;261(5122):769–771. doi: 10.1126/science.8342042. [DOI] [PubMed] [Google Scholar]
  23. Neefjes J. J., Ploegh H. L. Allele and locus-specific differences in cell surface expression and the association of HLA class I heavy chain with beta 2-microglobulin: differential effects of inhibition of glycosylation on class I subunit association. Eur J Immunol. 1988 May;18(5):801–810. doi: 10.1002/eji.1830180522. [DOI] [PubMed] [Google Scholar]
  24. Neisig A., Roelse J., Sijts A. J., Ossendorp F., Feltkamp M. C., Kast W. M., Melief C. J., Neefjes J. J. Major differences in transporter associated with antigen presentation (TAP)-dependent translocation of MHC class I-presentable peptides and the effect of flanking sequences. J Immunol. 1995 Feb 1;154(3):1273–1279. [PubMed] [Google Scholar]
  25. Niedermann G., Butz S., Ihlenfeldt H. G., Grimm R., Lucchiari M., Hoschützky H., Jung G., Maier B., Eichmann K. Contribution of proteasome-mediated proteolysis to the hierarchy of epitopes presented by major histocompatibility complex class I molecules. Immunity. 1995 Mar;2(3):289–299. doi: 10.1016/1074-7613(95)90053-5. [DOI] [PubMed] [Google Scholar]
  26. Oukka M., Riché N., Kosmatopoulos K. A nonimmunodominant nucleoprotein-derived peptide is presented by influenza A virus-infected H-2b cells. J Immunol. 1994 May 15;152(10):4843–4851. [PubMed] [Google Scholar]
  27. Schumacher T. N., Heemels M. T., Neefjes J. J., Kast W. M., Melief C. J., Ploegh H. L. Direct binding of peptide to empty MHC class I molecules on intact cells and in vitro. Cell. 1990 Aug 10;62(3):563–567. doi: 10.1016/0092-8674(90)90020-f. [DOI] [PubMed] [Google Scholar]
  28. Sheil J. M., Shepherd S. E., Klimo G. F., Paterson Y. Identification of an autologous insulin B chain peptide as a target antigen for H-2Kb-restricted cytotoxic T lymphocytes. J Exp Med. 1992 Feb 1;175(2):545–552. doi: 10.1084/jem.175.2.545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Shepherd J. C., Schumacher T. N., Ashton-Rickardt P. G., Imaeda S., Ploegh H. L., Janeway C. A., Jr, Tonegawa S. TAP1-dependent peptide translocation in vitro is ATP dependent and peptide selective. Cell. 1993 Aug 13;74(3):577–584. doi: 10.1016/0092-8674(93)80058-m. [DOI] [PubMed] [Google Scholar]
  30. Sijts A. J., Ossendorp F., Mengedé E. A., van den Elsen P. J., Melief C. J. Immunodominant mink cell focus-inducing murine leukemia virus (MuLV)-encoded CTL epitope, identified by its MHC class I-binding motif, explains MuLV-type specificity of MCF-directed cytotoxic T lymphocytes. J Immunol. 1994 Jan 1;152(1):106–116. [PubMed] [Google Scholar]
  31. Townsend A. R., Bastin J., Gould K., Brownlee G. G. Cytotoxic T lymphocytes recognize influenza haemagglutinin that lacks a signal sequence. Nature. 1986 Dec 11;324(6097):575–577. doi: 10.1038/324575a0. [DOI] [PubMed] [Google Scholar]
  32. Townsend A., Ohlén C., Bastin J., Ljunggren H. G., Foster L., Kärre K. Association of class I major histocompatibility heavy and light chains induced by viral peptides. Nature. 1989 Aug 10;340(6233):443–448. doi: 10.1038/340443a0. [DOI] [PubMed] [Google Scholar]
  33. Wettstein P. J., van Bleek G. M., Nathenson S. G. Differential binding of a minor histocompatibility antigen peptide to H-2 class I molecules correlates with immune responsiveness. J Immunol. 1993 Apr 1;150(7):2753–2760. [PubMed] [Google Scholar]
  34. Wipke B. T., Jameson S. C., Bevan M. J., Pamer E. G. Variable binding affinities of listeriolysin O peptides for the H-2Kd class I molecule. Eur J Immunol. 1993 Aug;23(8):2005–2010. doi: 10.1002/eji.1830230842. [DOI] [PubMed] [Google Scholar]
  35. Yao Z., Volgger A., Scholz S., Bönisch J., Albert E. D. Nucleotide sequence of a novel HLA-B44 subtype B*4405. Immunogenetics. 1994;40(4):310–310. doi: 10.1007/BF00189980. [DOI] [PubMed] [Google Scholar]

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