Superantigens as vaccine delivery vehicles for the generation of cellular immune responses

The constant battle between pathogen and host has led to substantial diversity and adaptability of the host immune system. Pathogens too, have evolved unique mechanisms to evade their hosts. The production of superantigens is one of these mechanisms. Superantigens are potent T cell mitogens that have the unique ability to bind simultaneously to major histocompatibility complex (MHC) class II molecules and T cell receptors (TCRs). The resulting uncontrolled activation of up to 20% of all T cells and the subsequent cytokine release, can lead to fever, shock and death. Superantigens are not processed intracellularly like conventional antigens but instead bind as intact proteins to MHC class II molecules expressed on the surface of professional antigen presenting cells. On the hypothesis that the unique properties of superantigens may serve useful for vaccine delivery, several bacterial superantigens were selectively mutated at their TCR-binding site with the ultimate goal of creating a safe, non-toxic carrier protein that could target antigen presenting cells by binding to MHC class II. Antigen presenting cells that expressed MHC class II were indeed targeted by the TCR-binding-deficient superantigens. Cellular internalisation of the superantigen into vesicles was observed as early as 30 min. These supcrantigens were also shown to traffic to, and be captured by, the lymph nodes of immunised mice. Using TCR-binding-deficicnt superantigens as vaccine carrier proteins, enhanced antigenicity and immunogenicity of the conjugated MHC class I-restricted peptide antigen. GP33, was observed in a mouse model. In vitro studies revealed up to 200-fold enhancement of antigenicity when GP33 was conjugated to superantigen. Enhanced immunogenicity was also observed in vivo, with conjugates providing protection against Lymphocytic choriomeningitis virus infection after only a single immunisation. These results indicate that modified superantigens are able to safely deliver peptides for cross-presentation, and may serve as a novel mechanism for vaccine delivery.

Name thesis:degree_name

PhD

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Molecular Medicine and Pathology

Grantor dc:publisher

ResearchSpace@Auckland

Year dc:date.issued

2006

Author dc:creator

• Loh, Mei San

Advisors dc:contributor.advisor

• Birgit Schrage
• Diana Schuhbauer

Statement dc:rights

• Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Licence dc:rights.uri

• https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm

Language dc:language.iso

en

Handle dc:identifier.uri

https://hdl.handle.net/2292/3161

OAI identifier oai:identifier

oai:researchspace.auckland.ac.nz:2292/3161