1887

Abstract

The hepatitis B virus (HBV) core antigen (HBcAg) has a unique ability to bind a high frequency of naive human and murine B cells. The role of HBcAg-binding naive B cells in the immunogenicity of HBcAg is not clear. The HBcAg-binding properties of naive B cells were characterized using HBcAg particles with mutated spike region (residues 76–85) sequences. Deletion of residues 76–85 (HBcΔ76–85) destroyed naive B cell binding, whereas deletion of residues 79–85 did not. HBcAg particles with an Ile instead of the natural Ala at position 80 did not bind naive B cells, whereas reversion of Ile→Ala restored B cell binding. Destroying the B cell-binding ability of HBcAg had a marginal effect on the overall B cell immunogenicity of the different particles, suggesting that they were equally efficient in priming T helper cells. Therefore, the importance of HBcAg-binding B cells is studied with relation to the priming of HBcAg-specific cytotoxic T cells (CTLs). The role of HBcAg-binding B cells in the priming of HBcAg-specific CTLs was evaluated by immunization with endogenous HBcAg (DNA immunization) and exogenous recombinant HBcAg particles. Endogenous HBcAg primed HBcAg-specific CTLs in wild-type and B cell-deficient mice, whereas exogenous HBcAg primed HBcAg-specific CTLs only in wild-type mice. Importantly, HBcΔ76–85 did not prime CTLs despite the presence of B cells. Thus, the ability of exogenous HBcAg particles to prime specific CTLs is B cell dependent, suggesting a possible role for HBcAg-binding B cells in HBV infections.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.18678-0
2003-01-01
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/jgv/84/1/vir840139.html?itemId=/content/journal/jgv/10.1099/vir.0.18678-0&mimeType=html&fmt=ahah

References

  1. Barnaba V., Franco A., Alberti A., Benvenuto R., Balsano F. 1990; Selective killing of hepatitis B envelope antigen-specific B cells by class I-restricted, exogenous antigen-specific T lymphocytes. Nature 345:258–260
    [Google Scholar]
  2. Bennett S. R., Carbone F. R., Toy T., Miller J. F., Heath W. R. 1998; B cells directly tolerize CD8+ T cells. J Exp Med 188:1977–1983
    [Google Scholar]
  3. Bichko V., Pushko P., Dreilina D., Pumpen P., Gren E. 1985; Subtype ayw variant of hepatitis B virus. DNA primary structure analysis. FEBS Lett 185:208–212
    [Google Scholar]
  4. Bottcher B., Wynne S. A., Crowther R. A. 1997; Determination of the fold of the core protein of hepatitis B virus by electron cryomicroscopy. Nature 386:88–91
    [Google Scholar]
  5. Cao T., Lazdina U., Desombere I., Vanlandschoot P., Milich D. R., Sallberg M., Leroux-Roels G. 2001; Hepatitis B virus core antigen binds and activates naive human B cells in vivo : studies with a human PBL-NOD/SCID mouse model. J Virol 75:6359–6366
    [Google Scholar]
  6. Carbone F. R., Kurts C., Bennett S. R., Miller J. F., Heath W. R. 1998; Cross-presentation: a general mechanism for CTL immunity and tolerance. Immunol Today 19:368–373
    [Google Scholar]
  7. Fehr T., Skrastina D., Pumpens P., Zinkernagel R. M. 1998; T cell-independent type I antibody response against B cell epitopes expressed repetitively on recombinant virus particles. Proc Natl Acad Sci U S A 95:9477–9481
    [Google Scholar]
  8. Jin L., Peterson D. L. 1995; Expression, isolation, and characterization of the hepatitis C virus ATPase/RNA helicase. Arch Biochem Biophys 323:47–53
    [Google Scholar]
  9. Karre K., Ljunggren H. G., Piontek G., Kiessling R. 1986; Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature 319:675–678
    [Google Scholar]
  10. Kast W. M., Roux L., Curren J., Blom H. J., Voordouw A. C., Meloen R. H., Kolakofsky D., Melief C. J. 1991; Protection against lethal Sendai virus infection by in vivo priming of virus-specific cytotoxic T lymphocytes with a free synthetic peptide. Proc Natl Acad Sci U S A 88:2283–2287
    [Google Scholar]
  11. Ke Y., Kapp J. A. 1996; Exogenous antigens gain access to the major histocompatibility complex class I processing pathway in B cells by receptor-mediated uptake. J Exp Med 184:1179–1184
    [Google Scholar]
  12. Kitamura D., Roes J., Kuhn R., Rajewsky K. 1991; A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene. Nature 350:423–426
    [Google Scholar]
  13. Kuhober A., Pudollek H. P., Reifenberg K., Chisari F. V., Schlicht H. J., Reimann J., Schirmbeck R. 1996; DNA immunization induces antibody and cytotoxic T cell responses to hepatitis B core antigen in H-2b mice. J Immunol 156:3687–3695
    [Google Scholar]
  14. Lazdina U., Cao T., Steinbergs J., Alheim M., Pumpens P., Peterson D. L., Milich D. R., Leroux-Roels G., Sallberg M. 2001a; Molecular basis for the interaction of the hepatitis B virus core antigen with the surface immunoglobulin receptor on naive B cells. J Virol 75:6367–6374
    [Google Scholar]
  15. Lazdina U., Hultgren C., Frelin L. 8 other authors 2001b; Humoral and CD4+ T helper (Th) cell responses to the hepatitis C virus non-structural 3 (NS3) protein: NS3 primes Th1-like responses more effectively as a DNA-based immunogen than as a recombinant protein. J Gen Virol 82:1299–1308
    [Google Scholar]
  16. Milich D. R., McLachlan A. 1986; The nucleocapsid of hepatitis B virus is both a T-cell-independent and a T-cell-dependent antigen. Science 234:1398–1401
    [Google Scholar]
  17. Milich D. R., Jones J. E., Hughes J. L., Price J., Raney A. K., McLachlan A. 1990; Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in utero?. Proc Natl Acad Sci U S A 87:6599–6603
    [Google Scholar]
  18. Milich D. R., Chen M., Schodel F., Peterson D. L., Jones J. E., Hughes J. L. 1997; Role of B cells in antigen presentation of the hepatitis B core. Proc Natl Acad Sci U S A 94:14648–14653
    [Google Scholar]
  19. Pushko P., Sallberg M., Borisova G., Ruden U., Bichko V., Wahren B., Pumpens P., Magnius L. 1994; Identification of hepatitis B virus core protein regions exposed or internalized at the surface of HBcAg particles by scanning with monoclonal antibodies. Virology 202:912–920
    [Google Scholar]
  20. Reimann J., Schirmbeck R. 1999; Alternative pathways for processing exogenous and endogenous antigens that can generate peptides for MHC class I-restricted presentation. Immunol Rev 172:131–152
    [Google Scholar]
  21. Salfeld J., Pfaff E., Noah M., Schaller H. 1989; Antigenic determinants and functional domains in core antigen and e antigen from hepatitis B virus. J Virol 63:798–808
    [Google Scholar]
  22. Sallberg M., Ruden U., Magnius L. O., Harthus H. P., Noah M., Wahren B. 1991; Characterisation of a linear binding site for a monoclonal antibody to hepatitis B core antigen. J Med Virol 33:248–252
    [Google Scholar]
  23. Sallberg M., Pushko P., Berzinsh I., Bichko V., Sillekens P., Noah M., Pumpens P., Grens E., Wahren B., Magnius L. O. 1993; Immunochemical structure of the carboxy-terminal part of hepatitis B e antigen: identification of internal and surface-exposed sequences. J Gen Virol 74:1335–1340
    [Google Scholar]
  24. Sandberg J. K., Franksson L., Sundback J. 10 other authors 2000; T cell tolerance based on avidity thresholds rather than complete deletion allows maintenance of maximal repertoire diversity. J Immunol 165:25–33
    [Google Scholar]
  25. Schodel F., Peterson D., Zheng J., Jones J. E., Hughes J. L., Milich D. R. 1993; Structure of hepatitis B virus core and e antigen. A single precore amino acid prevents nucleocapsid assembly. J Biol Chem 268:1332–1337
    [Google Scholar]
  26. Schodel F., Peterson D., Milich D. 1996; Hepatitis B virus core and e antigen: immune recognition and use as a vaccine carrier moiety. Intervirology 39:104–110
    [Google Scholar]
  27. Schumacher T. N., De Bruijn M. L., Vernie L. N., Kast W. M., Melief C. J., Neefjes J. J., Ploegh H. L. 1991; Peptide selection by MHC class I molecules. Nature 350:703–706
    [Google Scholar]
  28. Schuurhuis D. H., Ioan-Facsinay A., Nagelkerken B., van Schip J. J., Sedlik C., Melief C. J., Verbeek J. S., Ossendorp F. 2002; Antigen–antibody immune complexes empower dendritic cells to efficiently prime specific CD8+ CTL responses in vivo . J Immunol 168:2240–2246
    [Google Scholar]
  29. Storni T., Lechner F., Erdmann I., Bachi T., Jegerlehner A., Dumrese T., Kundig T. M., Ruedl C., Bachmann M. F. 2002; Critical role for activation of antigen-presenting cells in priming of cytotoxic T cell responses after vaccination with virus-like particles. J Immunol 168:2880–2886
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.18678-0
Loading
/content/journal/jgv/10.1099/vir.0.18678-0
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error