An engineered non-toxic superantigen increases cross presentation of hepatitis B virus nucleocapsids by human dendritic cells

PLoS One. 2014 Apr 1;9(4):e93598. doi: 10.1371/journal.pone.0093598. eCollection 2014.

Abstract

Virus like particles (VLPs) are potent immunogens capable of priming strong protective antibody responses due to their repetitive structural arrangement and affinity for specific B cell receptors. By contrast, T cell responses to VLPs can be weak due to inefficient uptake and processing by antigen presenting cells. We report here a novel strategy for increasing the T cell reactivity of a VLP, the nucleocapsid of hepatitis B virus, through covalent coupling of M1, an engineered form of the Streptococcal superantigen SMEZ2, that binds MHC II with high affinity but lacks its T cell mitogenic capability. M1:HBcAg conjugates bound to dendritic cells and were efficiently endocytosed into late endosomes. Human dendritic cells pulsed with M1:HBcAgs stimulated HBV-specific CD8(+) T cells more effectively than cells pulsed with native capsids indicating that the modified VLP was more effectively cross presented by APCs. Coupling of M1 was also able to induce significantly greater reactivity of human CD4(+) T cells specific for a common T-helper epitope. These studies indicate the potential of recombinant superantigens to act as flexible molecular adjuvants that can be incorporated into various subunit vaccine platforms leading to enhanced T cell reactivity in humans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigen-Presenting Cells / immunology
  • Bacterial Toxins / genetics
  • Bacterial Toxins / immunology
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Dendritic Cells / immunology*
  • Epitopes / genetics
  • Epitopes / immunology
  • Exotoxins / genetics
  • Exotoxins / immunology
  • Hepatitis B / immunology*
  • Hepatitis B / prevention & control
  • Hepatitis B / virology
  • Hepatitis B Core Antigens / immunology
  • Hepatitis B virus / genetics
  • Hepatitis B virus / immunology*
  • Hepatitis B virus / pathogenicity
  • Humans
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology
  • Nucleocapsid / genetics
  • Nucleocapsid / immunology*
  • Superantigens / genetics
  • Superantigens / immunology*
  • Vaccines, Virus-Like Particle / genetics
  • Vaccines, Virus-Like Particle / immunology

Substances

  • Bacterial Toxins
  • Epitopes
  • Exotoxins
  • Hepatitis B Core Antigens
  • Superantigens
  • Vaccines, Virus-Like Particle
  • mitogenic exotoxin Z protein, Streptococcus

Grant support

This research was funded by a Project Grant awarded by the Health Research Council of New Zealand (05/252). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.