Interaction of the hepatitis B core antigen and the innate immune system.
Previous studies demonstrated that the primary APCs for the hepatitis B core Ag (HBcAg) were B cells and not dendritic cells (DC). We now report that splenic B1a and B1b cells more efficiently present soluble HBcAg to naive CD4(+) T cells than splenic B2 cells. This was demonstrated by direct HBcAg-biotin-binding studies and by HBcAg-specific T cell activation in vitro in cultures of naive HBcAg-specific T cells and resting B cell subpopulations. The inability of DC to function as APCs for exogenous HBcAg relates to lack of uptake of HBcAg, not to processing or presentation, because HBcAg/anti-HBc immune complexes can be efficiently presented by DC. Furthermore, HBcAg-specific CD4(+) and CD8(+) T cell priming with DNA encoding HBcAg does not require B cell APCs. TLR activation, another innate immune response, was also examined. Full-length (HBcAg(183)), truncated (HBcAg(149)), and the nonparticulate HBeAg were screened for TLR stimulation via NF-kappaB activation in HEK293 cells expressing human TLRs. None of the HBc/HBeAgs activated human TLRs. Therefore, the HBc/HBeAg proteins are not ligands for human TLRs. However, the ssRNA contained within HBcAg(183) does function as a TLR-7 ligand, as demonstrated at the T and B cell levels in TLR-7 knockout mice. Bacterial, yeast, and mammalian ssRNA encapsidated within HBcAg(183) all function as TLR-7 ligands. These studies indicate that innate immune mechanisms bridge to and enhance the adaptive immune response to HBcAg and have important implications for the use of hepadnavirus core proteins as vaccine carrier platforms.
Lee
Byung O
BO
Vaccine Research Institute of San Diego, San Diego, CA 92109, USA.
Tucker
Amy
A
Frelin
Lars
L
Sallberg
Matti
M
Jones
Joyce
J
Peters
Cory
C
Hughes
Janice
J
Whitacre
David
D
Darsow
Bryan
B
Peterson
Darrell L
DL
Milich
David R
DR
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D001402:B-Lymphocytes / Q000145:classification / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D006512:Hepatitis B Core Antigens / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D051199:Toll-Like Receptor 7 / Q000276:immunology* / Q000378:metabolism
D006512:Hepatitis B Core Antigens; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D012367:RNA, Viral; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7