Home LiteratureArticle Details
PMID: 14504389 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Interference with T cell receptor-HLA-DR interactions by Epstein-Barr virus gp42 results in reduced T helper cell recognition.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 100 ·No. 20 ·2003-09-30 ·Pages 11583-8

Ressing ME, van Leeuwen D, Verreck FA, Gomez R, Heemskerk B, Toebes M, Mullen MM, Jardetzky TS, Longnecker R, Schilham MW, Ottenhoff TH, Neefjes J, Schumacher TN, Hutt-Fletcher LM, Wiertz EJ

Abstract

Epstein-Barr virus (EBV) persists lifelong in infected hosts despite the presence of antiviral immunity. Many viral antigens are expressed during lytic infection. Thus, for EBV to spread, it must have evolved effective ways to evade immune recognition. Here, we report that HLA class II-restricted antigen presentation to T helper cells is hampered in the presence of the lytic-phase protein gp42. This interference with T cell activation involves association of gp42 with class II peptide complexes. Using HLA-DR tetramers, we identify a block in T cell receptor (TCR)-class II interactions imposed by gp42 as the underlying mechanism. EBV gp42 sterically clashes with TCR Valpha-domains as visualized by superimposing the crystal structures for gp42-HLA-DR1 and TCR-MHC class II complexes. Blocking TCR recognition provides a previously undescribed strategy for viral immune evasion.

MeSH Terms
Flow Cytometry HLA-DR Antigens/immunology Humans Models, Molecular Receptors, Antigen, T-Cell/immunology T-Lymphocytes, Helper-Inducer/immunology Tumor Cells, Cultured Viral Proteins/chemistry,immunology
Chemicals
HLA-DR Antigens Receptors, Antigen, T-Cell Viral Proteins
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Ressing Maaike E
Department of Medical Microbiology, Immunohematology and Blood Transfusion, and Pediatrics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
van Leeuwen Daphne
Verreck Frank A W
Gomez Raquel
Heemskerk Bianca
Toebes Mireille
Mullen Maureen M
Jardetzky Theodore S
Longnecker Richard
Schilham Marco W
Ottenhoff Tom H M
Neefjes Jacques
Schumacher Ton N
Hutt-Fletcher Lindsey M
Wiertz Emmanuel J H J
References (44)
44 references, click to expand
  1. The crystal structure of a T cell receptor in complex with peptide and MHC class II.
    Science. 1999 Dec 3;286(5446):1913-21 PMID: 10583947
  2. Phenotypic analysis of antigen-specific T lymphocytes.
    Science. 1996 Oct 4;274(5284):94-6 PMID: 8810254
  3. Human CD4(+) T lymphocytes consistently respond to the latent Epstein-Barr virus nuclear antigen EBNA1.
    J Exp Med. 2000 May 15;191(10):1649-60 PMID: 10811859
  4. Viral subversion of the immune system.
    Annu Rev Immunol. 2000;18:861-926 PMID: 10837078
  5. Coreceptor restriction within the HLA-DQ locus for Epstein-Barr virus infection.
    Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):9252-7 PMID: 10908662
  6. Structure of a covalently stabilized complex of a human alphabeta T-cell receptor, influenza HA peptide and MHC class II molecule, HLA-DR1.
    EMBO J. 2000 Nov 1;19(21):5611-24 PMID: 11060013
  7. Inhibition of IFN-gamma signaling by an Epstein-Barr virus immediate-early protein.
    Immunity. 2001 Nov;15(5):787-99 PMID: 11728340
  8. Structure of the Epstein-Barr virus gp42 protein bound to the MHC class II receptor HLA-DR1.
    Mol Cell. 2002 Feb;9(2):375-85 PMID: 11864610
  9. Structure of a complex of the human alpha/beta T cell receptor (TCR) HA1.7, influenza hemagglutinin peptide, and major histocompatibility complex class II molecule, HLA-DR4 (DRA*0101 and DRB1*0401): insight into TCR cross-restriction and alloreactivity.
    J Exp Med. 2002 Mar 4;195(5):571-81 PMID: 11877480
  10. Epitope-specific evolution of human CD8(+) T cell responses from primary to persistent phases of Epstein-Barr virus infection.
    J Exp Med. 2002 Apr 1;195(7):893-905 PMID: 11927633
  11. Alternate replication in B cells and epithelial cells switches tropism of Epstein-Barr virus.
    Nat Med. 2002 Jun;8(6):594-9 PMID: 12042810
  12. T cell receptor-MHC interactions up close.
    Cell. 2001 Jan 12;104(1):1-4 PMID: 11163234
  13. Conformational alterations during biosynthesis of HLA-DR3 molecules controlled by invariant chain and HLA-DM.
    Eur J Immunol. 2001 Apr;31(4):1029-36 PMID: 11298327
  14. Dysfunctional Epstein-Barr virus (EBV)-specific CD8(+) T lymphocytes and increased EBV load in HIV-1 infected individuals progressing to AIDS-related non-Hodgkin lymphoma.
    Blood. 2001 Jul 1;98(1):146-55 PMID: 11418474
  15. Differential immunogenicity of Epstein-Barr virus latent-cycle proteins for human CD4(+) T-helper 1 responses.
    J Virol. 2001 Sep;75(18):8649-59 PMID: 11507210
  16. HIV-1 Nef impairs MHC class II antigen presentation and surface expression.
    Proc Natl Acad Sci U S A. 2001 Oct 9;98(21):12144-9 PMID: 11593029
  17. Progressive loss of CD8+ T cell-mediated control of a gamma-herpesvirus in the absence of CD4+ T cells.
    J Exp Med. 1996 Sep 1;184(3):863-71 PMID: 9064346
  18. MHC class II restricted antigen presentation.
    Curr Opin Immunol. 1997 Feb;9(1):89-96 PMID: 9039772
  19. Class I processing-defective Burkitt's lymphoma cells are recognized efficiently by CD4+ EBV-specific CTLs.
    J Immunol. 1997 Apr 15;158(8):3619-25 PMID: 9103423
  20. Human cytotoxic T lymphocyte responses to Epstein-Barr virus infection.
    Annu Rev Immunol. 1997;15:405-31 PMID: 9143694
  21. Epstein-Barr virus uses HLA class II as a cofactor for infection of B lymphocytes.
    J Virol. 1997 Jun;71(6):4657-62 PMID: 9151859
  22. Immediate early and early lytic cycle proteins are frequent targets of the Epstein-Barr virus-induced cytotoxic T cell response.
    J Exp Med. 1997 May 5;185(9):1605-17 PMID: 9151898
  23. HLA-DO is a negative modulator of HLA-DM-mediated MHC class II peptide loading.
    Curr Biol. 1997 Dec 1;7(12):950-7 PMID: 9382849
  24. Epstein-Barr virus lacking glycoprotein gp42 can bind to B cells but is not able to infect.
    J Virol. 1998 Jan;72(1):158-63 PMID: 9420211
  25. Enrichment of an antigen-specific T cell response by retrovirally transduced human dendritic cells.
    Cell Immunol. 1999 Jul 10;195(1):10-7 PMID: 10433792
  26. The biology of Epstein-Barr virus: lessons learned from the virus and the host.
    Curr Opin Immunol. 1999 Aug;11(4):365-70 PMID: 10448133
  27. Cytomegalovirus US2 destroys two components of the MHC class II pathway, preventing recognition by CD4+ T cells.
    Nat Med. 1999 Sep;5(9):1039-43 PMID: 10470081
  28. The lytic cycle of Epstein-Barr virus is associated with decreased expression of cell surface major histocompatibility complex class I and class II molecules.
    J Virol. 2002 Aug;76(16):8179-88 PMID: 12134023
  29. Differential kinetics of antigen-specific CD4+ and CD8+ T cell responses in the regression of retrovirus-induced sarcomas.
    J Immunol. 2002 Sep 15;169(6):3191-9 PMID: 12218137
  30. Manipulation of immune responses by Epstein-Barr virus.
    Virus Res. 2002 Sep;88(1-2):71-86 PMID: 12297328
  31. Inhibition of HLA-DR assembly, transport, and loading by human cytomegalovirus glycoprotein US3: a novel mechanism for evading major histocompatibility complex class II antigen presentation.
    J Virol. 2002 Nov;76(21):10929-41 PMID: 12368336
  32. Extensive cross-reactivity of CD4+ adenovirus-specific T cells: implications for immunotherapy and gene therapy.
    J Virol. 2003 Jun;77(11):6562-6 PMID: 12743315
  33. Synchronous and sequential activation of latently infected Epstein-Barr virus genomes.
    J Virol. 1989 Jan;63(1):445-9 PMID: 2462063
  34. Three pathways of Epstein-Barr virus gene activation from EBNA1-positive latency in B lymphocytes.
    J Virol. 1992 Jan;66(1):122-31 PMID: 1309242
  35. Inhibition of endosomal proteolytic activity by leupeptin blocks surface expression of MHC class II molecules and their conversion to SDS resistance alpha beta heterodimers in endosomes.
    EMBO J. 1992 Feb;11(2):411-6 PMID: 1311249
  36. Functional analysis of DR17(DR3)-restricted mycobacterial T cell epitopes reveals DR17-binding motif and enables the design of allele-specific competitor peptides.
    J Immunol. 1992 Nov 1;149(9):2864-71 PMID: 1383331
  37. Epstein-Barr virus (EBV) latent membrane protein 1 increases HLA class II expression in an EBV-negative B cell line.
    Eur J Immunol. 1994 Jun;24(6):1467-70 PMID: 8206105
  38. Assembly, transport, and function of MHC class II molecules.
    Annu Rev Immunol. 1994;12:259-93 PMID: 8011283
  39. The Epstein-Barr virus (EBV) BZLF2 gene product associates with the gH and gL homologs of EBV and carries an epitope critical to infection of B cells but not of epithelial cells.
    J Virol. 1995 Jul;69(7):3987-94 PMID: 7539502
  40. Restoration of endogenous antigen processing in Burkitt's lymphoma cells by Epstein-Barr virus latent membrane protein-1: coordinate up-regulation of peptide transporters and HLA-class I antigen expression.
    Eur J Immunol. 1995 May;25(5):1374-84 PMID: 7774641
  41. Assembly and intracellular transport of HLA-DM and correction of the class II antigen-processing defect in T2 cells.
    Immunity. 1994 Oct;1(7):595-606 PMID: 7600288
  42. The human cytomegalovirus US11 gene product dislocates MHC class I heavy chains from the endoplasmic reticulum to the cytosol.
    Cell. 1996 Mar 8;84(5):769-79 PMID: 8625414
  43. The extracellular domain of the Epstein-Barr virus BZLF2 protein binds the HLA-DR beta chain and inhibits antigen presentation.
    J Virol. 1996 Aug;70(8):5557-63 PMID: 8764069
  44. MHC class II tetramers identify peptide-specific human CD4(+) T cells proliferating in response to influenza A antigen.
    J Clin Invest. 1999 Dec;104(12):R63-7 PMID: 10606632
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.2034960100
Published
2003-09-30
Epub
2003-00-22
Pages
11583-8
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC208801
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.2034960100 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2