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 Ile80→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.
BarnabaV.,
FrancoA.,
AlbertiA.,
BenvenutoR.,
BalsanoF.1990; Selective killing of hepatitis B envelope antigen-specific B cells by class I-restricted, exogenous antigen-specific T lymphocytes. Nature 345:258–260
BottcherB.,
WynneS. A.,
CrowtherR. A.1997; Determination of the fold of the core protein of hepatitis B virus by electron cryomicroscopy. Nature 386:88–91
CaoT.,
LazdinaU.,
DesombereI.,
VanlandschootP.,
MilichD. R.,
SallbergM.,
Leroux-RoelsG.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
CarboneF. R.,
KurtsC.,
BennettS. R.,
MillerJ. F.,
HeathW. R.1998; Cross-presentation: a general mechanism for CTL immunity and tolerance. Immunol Today 19:368–373
FehrT.,
SkrastinaD.,
PumpensP.,
ZinkernagelR. 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
KastW. M.,
RouxL.,
CurrenJ.,
BlomH. J.,
VoordouwA. C.,
MeloenR. H.,
KolakofskyD.,
MeliefC. 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
KeY.,
KappJ. 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
KitamuraD.,
RoesJ.,
KuhnR.,
RajewskyK.1991; A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene. Nature 350:423–426
KuhoberA.,
PudollekH. P.,
ReifenbergK.,
ChisariF. V.,
SchlichtH. J.,
ReimannJ.,
SchirmbeckR.1996; DNA immunization induces antibody and cytotoxic T cell responses to hepatitis B core antigen in H-2b mice. J Immunol 156:3687–3695
LazdinaU.,
CaoT.,
SteinbergsJ.,
AlheimM.,
PumpensP.,
PetersonD. L.,
MilichD. R.,
Leroux-RoelsG.,
SallbergM.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
LazdinaU.,
HultgrenC.,
FrelinL.8 other authors2001b; 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
MilichD. R.,
JonesJ. E.,
HughesJ. L.,
PriceJ.,
RaneyA. K.,
McLachlanA.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
MilichD. R.,
ChenM.,
SchodelF.,
PetersonD. L.,
JonesJ. E.,
HughesJ. L.1997; Role of B cells in antigen presentation of the hepatitis B core. Proc Natl Acad Sci U S A 94:14648–14653
PushkoP.,
SallbergM.,
BorisovaG.,
RudenU.,
BichkoV.,
WahrenB.,
PumpensP.,
MagniusL.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
ReimannJ.,
SchirmbeckR.1999; Alternative pathways for processing exogenous and endogenous antigens that can generate peptides for MHC class I-restricted presentation. Immunol Rev 172:131–152
SalfeldJ.,
PfaffE.,
NoahM.,
SchallerH.1989; Antigenic determinants and functional domains in core antigen and e antigen from hepatitis B virus. J Virol 63:798–808
SallbergM.,
RudenU.,
MagniusL. O.,
HarthusH. P.,
NoahM.,
WahrenB.1991; Characterisation of a linear binding site for a monoclonal antibody to hepatitis B core antigen. J Med Virol 33:248–252
SallbergM.,
PushkoP.,
BerzinshI.,
BichkoV.,
SillekensP.,
NoahM.,
PumpensP.,
GrensE.,
WahrenB.,
MagniusL. 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
SandbergJ. K.,
FrankssonL.,
SundbackJ.10 other authors2000; T cell tolerance based on avidity thresholds rather than complete deletion allows maintenance of maximal repertoire diversity. J Immunol 165:25–33
SchodelF.,
PetersonD.,
ZhengJ.,
JonesJ. E.,
HughesJ. L.,
MilichD. 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
SchodelF.,
PetersonD.,
MilichD.1996; Hepatitis B virus core and e antigen: immune recognition and use as a vaccine carrier moiety. Intervirology 39:104–110
SchumacherT. N.,
De BruijnM. L.,
VernieL. N.,
KastW. M.,
MeliefC. J.,
NeefjesJ. J.,
PloeghH. L.1991; Peptide selection by MHC class I molecules. Nature 350:703–706
StorniT.,
LechnerF.,
ErdmannI.,
BachiT.,
JegerlehnerA.,
DumreseT.,
KundigT. M.,
RuedlC.,
BachmannM. 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