A function of the hepatitis B virus precore protein is to regulate the immune response to the core antigen.
A unique characteristic of the hepatitis B virus is the production of a secreted form (precore or HBeAg) of the structural nucleocapsid (core or HBcAg). By using T cell receptor (TCR) transgenic (Tg) and TCR x HBc/HBeAg double- and triple-Tg pairs, we demonstrate that HBeAg elicits T cell tolerance, whereas HBcAg is nontolerogenic in this system. In fact, TCR x HBc double-Tg mice spontaneously seroconvert to IgG anti-HBc positivity at an early age. However, the presence of HBeAg in the serum of TCR x HBc x HBe triple-Tg mice prevents anti-HBc seroconversion. HBeAg mediates its immunoregulatory effect by eliciting tolerance in HBc/HBeAg-specific T cells. The results suggest that hepadnaviruses have retained a secretory form of the nucleoprotein because it functions as a T cell tolerogen and regulates the immune response to the intracellular nucleocapsid. This HBeAg-mediated immune regulation may predispose to chronicity during perinatal infections and prevent severe liver injury during adult infections.
Karolinska Institute and Swedish Institute for Infectious Disease Control, 171 82 Solna, Sweden.
Margaret T
MT
Chen
Jean-Noel
JN
Billaud
Matti
M
Sällberg
Luca G
LG
Guidotti
Francis V
FV
Chisari
Joyce
J
Jones
Janice
J
Hughes
David R
DR
Milich
D019264:Adoptive Transfer; D000818:Animals; D017635:Clonal Anergy; D016207:Cytokines / Q000032:analysis; D006511:Hepatitis B Antigens / Q000276:immunology*; D006512:Hepatitis B Core Antigens / Q000276:immunology*; D006513:Hepatitis B e Antigens / Q000097:blood; D006515:Hepatitis B virus / Q000276:immunology*; D008099:Liver / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D011498:Protein Precursors / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D011994:Recombinant Proteins / Q000276:immunology; D013154:Spleen / Q000276:immunology / Q000637:transplantation; D013601:T-Lymphocytes / Q000276:immunology; D014758:Viral Core Proteins / Q000276:immunology*
D016207:Cytokines; D006511:Hepatitis B Antigens; D006512:Hepatitis B Core Antigens; D006513:Hepatitis B e Antigens; D011498:Protein Precursors; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; D014758:Viral Core Proteins