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.