Resolving the 'core' of influenza infection

Background - The internal elements of the Influenza-A virus, exhibit high levels of conservation and offer a more consistent target for the immune system amidst the diversity of potential strains. T-cell responses to these proteins have been shown to correlate with protection and deceased symptom severity during infection. Yet the epitopes and T-cell receptor (TCR) repertoires that underpin these important responses have not been analysed in detail at the molecular level. Results - These responses were analysed by the development of an HLA-DR1 restricted epitope mapping platform in chapter 3, followed by its application in finding DR1-restricted epitopes within the three internal proteins in chapter 4. Two of these epitopes were analysed by X-ray crystallography to understand their presentation and complement HLA-binding algorithm data. Identification of epitopes that gave robust and reproducible responses allowed analysis of responding T-cell populations by HLA-multimer staining on flow cytometry and subsequent clonotypic analysis of TCR repertoires in chapter 5. The clonotypic repertoire data was interpreted and then information in response to a single epitope was aligned with structural data in chapter 6 to further understand the molecular interactions that shape these responses. Conclusions - This work generated several novel HLA-DR1 restricted epitopes, crystal structures and TCR repertoire information that both expands existing knowledge of CD4+ T-cell responses, and confirms the potential of the conserved influenza proteins as targets in future vaccination research.