Priming of cytotoxic T cell responses to exogenous hepatitis B virus core antigen is B cell dependent

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 (HBcD76-85) 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 80 RAla 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, HBcD76-85 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 HBcAgbinding B cells in HBV infections.

Diagnosis, prevention and management of hepatitis B virus reactivation during anticancer therapy

“…[69][70] Although lysis of HBV-infected hepatocytes is mainly mediated by CD8ϩ cytotoxic T cell immunity, B cells may also act as antigen-presenting cells and prime cytotoxic T lymphocyte-specific responses in HBV infection. 71 This is supported by reports of rituximab-and alemtuzumab-induced severe or fatal cytomegalovirus reactivation, parvovirus B19 infection, adenovirus infection, and pneumocystis carinii pneumonia. 70,[72][73][74][75] The progressive B and T cell depletion may also account for the increasing incidence of HBV reactivation in anti-HBs-and/or anti-HBc-positive patients undergoing chemotherapy with these agents (Table 1B).…”

Development of a nasal vaccine for chronic hepatitis B infection that uses the ability of hepatitis B core antigen to stimulate a strong Th1 response against hepatitis B surface antigen

“…This result is in line with the finding that B cells that bind viral capsids can prime cytotoxic T cells. 43 We were also able to show that proliferative T-cell responses were enhanced using nasal administration of the combined HBs and HBc formulation. This was evident from the strong adjuvant effect of HBcAg on the cellular immune response against HBsAg and vice versa.…”

A fusion product of the complete Borrelia burgdorferi outer surface protein A (OspA) and the hepatitis B virus capsid protein is highly immunogenic and induces protective immunity similar to that seen with an effective lipidated OspA vaccine formula

“…Moreover, recent data indicate that HBcAg can also bind to and activate B cells via a linear motif present in the FR1-CDR1 junction of the heavy or light chain of the B cell surface receptor [26]. The latter process may also lead to the induction of co-stimulatory molecules required for efficient priming of Th cells [28,29].…”

“…Moreover, HBcAg directly binds to and activates a large fraction of naive B cells [25], both murine and human, via linear conserved regions of the Ig heavy and light chains [26]. Finally, HBcAg expresses multiple Th epitopes for CD4 + T cells [27][28][29].…”