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Molecular mechanisms underlying pMHC-II recognition

Schauenburg, Andrea J. A. 2016. Molecular mechanisms underlying pMHC-II recognition. PhD Thesis, Cardiff University.
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Abstract

The immune system is a complex network of cells and molecules working together with the purpose of fending off potentially harmful pathogens. CD4+ T cells take key roles within this network by orchestrating a multitude of its players. They recognise pathogen or self-derived peptides (p) bound to molecules of the major histocompatibility class II (MHC-II) through their T cell receptor (TCR). Cytokines secreted in response to recognition aid antibody production and cytotoxic T cell activity, both critical for anti-viral immunity. In this thesis, TCR/pMHC-II interactions were investigated using a range of functional and molecular approaches in order to gain valuable insight into the mechanisms underlying successful antigen recognition. To aid these investigations, a versatile, insect cell based expression system for HLA-DR1 was successfully implemented to generate soluble protein for use in multimer stainings and biophysical assays. Two HLA-DR1 restricted peptides encoded within influenza heamagglutinin (HA) were confirmed as being highly conserved making them ideal targets for vaccine development and allowing identification of influenza specific CD4+ T cells. Furthermore, the various roles of peptide flanking residues (PFR) were investigated using two experimental models. In a HA derived peptide, C-terminal PFR proved essential for peptide binding stability to HLA-DR1 and in consequence, CD4+ T cell activation. Clonotyping of CD4+ T cells grown against peptides of varying PFR lengths showed that TCR gene selection was heavily influenced by PFR. A HIV gag24 derived peptide displaying an unusual secondary structure within its N-terminal PFR gave further insight into how seemingly small modifications to PFR can have wide reaching impact on CD4+ T cell activation. Both studies highlighted the need for more in depths investigations into this emerging field and the wide reaching impacts of this inherent feature of MHC-II restricted peptides. Overall, the results in this thesis added novel insight into the mechanisms underlying TCR/pMHC-II interactions.

Item Type: Thesis (PhD)
Date Type: Publication
Status: Unpublished
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QR Microbiology > QR180 Immunology
Date of First Compliant Deposit: 23 November 2016
Last Modified: 05 Jun 2017 05:46
URI: http://orca.cf.ac.uk/id/eprint/96291

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