Induction of antigen-positive cell death by the expression of Perforin, but not DTa, from a DNA vaccine enhances the immune response

Tessa Gargett, Branka Grubor-Bauk, Tamsin J. Garrod, Wenbo Yu, Darren Miller, Lee Major, Steve Wesselingh, Andreas Suhrbier, Eric J. Gowans

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

The failure of traditional protein-based vaccines to prevent infection by viruses such as HIV or hepatitis C highlights the need for novel vaccine strategies. DNA vaccines have shown promise in small animal models, and are effective at generating anti-viral T cell-mediated immune responses; however, they have proved to be poorly immunogenic in clinical trials. We propose that the induction of necrosis will enhance the immune response to vaccine antigens encoded by DNA vaccines, as necrotic cells are known to release a range of intracellular factors that lead to dendritic cell (DC) activation and enhanced cross-presentation of antigen. Here we provide evidence that induction of cell death in DNA vaccine-targeted cells provides an adjuvant effect following intradermal vaccination of mice; however, this enhancement of the immune response is dependent on both the mechanism and timing of cell death after antigen expression. We report that a DNA vaccine encoding the cytolytic protein, perforin, resulted in DC activation, enhanced broad and multifunctional CD8 T-cell responses to the HIV-1 antigen GAG and reduced viral load following challenge with a chimeric virus, EcoHIV, compared with the canonical GAG DNA vaccine. This effect was not observed for a DNA vaccine encoding an apoptosis-inducing toxin, DTa, or when the level of perforin expression was increased to induce cell death sooner after vaccination. Thus, inducing lytic cell death following a threshold level of expression of a viral antigen can improve the immunogenicity of DNA vaccines, whereas apoptotic cell death has an inhibitory effect on the immune response.

LanguageEnglish
Pages359-367
Number of pages9
JournalImmunology and Cell Biology
Volume92
Issue number4
DOIs
Publication statusPublished - 1 Jan 2014

Keywords

  • DNA vaccines
  • T cells
  • cell death
  • dendritic cells

ASJC Scopus subject areas

  • Immunology
  • Cell Biology

Cite this

Gargett, Tessa ; Grubor-Bauk, Branka ; Garrod, Tamsin J. ; Yu, Wenbo ; Miller, Darren ; Major, Lee ; Wesselingh, Steve ; Suhrbier, Andreas ; Gowans, Eric J. / Induction of antigen-positive cell death by the expression of Perforin, but not DTa, from a DNA vaccine enhances the immune response. In: Immunology and Cell Biology. 2014 ; Vol. 92, No. 4. pp. 359-367.
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Induction of antigen-positive cell death by the expression of Perforin, but not DTa, from a DNA vaccine enhances the immune response. / Gargett, Tessa; Grubor-Bauk, Branka; Garrod, Tamsin J.; Yu, Wenbo; Miller, Darren; Major, Lee; Wesselingh, Steve; Suhrbier, Andreas; Gowans, Eric J.

In: Immunology and Cell Biology, Vol. 92, No. 4, 01.01.2014, p. 359-367.

Research output: Contribution to journalArticle

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