Microbiology & Immunology - Theses
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ItemAnalysis of factors influencing CD8+ T cell responses after influenza A virus infection( 2013)CD8+ T cell responses to pathogens are characterised by the clonal expansion of cells expressing T cell receptors (TCRs) of unique specificity for antigenic peptide (p) determinants presented by major histocompatibility complex (MHC) class I molecules. Following infection, the magnitude of various antigen-specific T cell responses often fall into a highly reproducible immunodominance hierarchy. Evidence suggests that the smaller, subdominant CD8+ T cell responses are important in the control of many viral infections, thus a better understanding of how these responses are generated may have implications for augmenting typically subdominant responses. Furthermore, epitope-specific CD8+ T cell populations expressing a diverse array of TCRs have been suggested to provide enhanced immunity to virus infection and reduced risk of immune evasion through viral escape mutations. However, there has been limited analysis of the usage and diversity of complete TCRαβ repertoires with previous examination generally restricted the TCRβ chain. It is vital to include the TCRα chain as there is increasing evidence to suggest that this chain is important in providing pMHC specificity. A better knowledge of the usage and diversity of complete TCRαβ repertoires will assist in the design of vaccine and immunotherapy protocols that make optimal use of the available T cell repertoire and provide effective immune protection. This thesis therefore assessed the roles of several determinants of subdominant epitope status and examined the usage and diversity of epitope-specific TCRαβ repertoires in response to viral infection. The role of naïve CD8+ T cell precursor (CTLp) frequency and epitope abundance as determinants of subdominant epitope status were examined. These studies demonstrated that the numbers of CTLps may control the early immunodominance hierarchy, with the level of epitope abundance on the surface of CD8+ T cells and the role of inefficient cell recruitment and clonal expansion a possible mechanisms for determining acute phase subdominant epitope status. Importantly, the role of the various determinants of immunodominance may contribute differently for each epitope specificity. The importance of the TCRα and TCRβ chains in determining TCR specific and repertoire diversity was investigated though the examination of the complete TCRαβ repertoire of epitope-specific CD8+ T cell populations. This investigation highlighted the necessity for complete characterisation of the responding TCRαβ heterodimers, rather than just the individual TCRα or TCRβ chains. This was due to the TCRβ repertoire of an epitope-specific CD8+ T cell population (the influenza-derived DbNP366-specific set) not reflecting the characteristics of the complete TCRαβ repertoire. The TCRαβ chains were shown to be vital in conferring pMHC specificity. This high degree of specificity is generally achieved through the biased usage of particular V and J gene segments which appear to offer the appropriate structural characteristics for optimal recognition, whilst diversity is maintained thought the use of varying amino acid sequences in the complementarity determining region-3 (CDR3). Though the examination of the selection of particular T cells during various stages of an immune response the responding epitope-specific CD8+ T cell response was shown to select T cells that are capable of optimal antigen recognition and may offer the greatest protection against infection. However, the overall extent of TCR diversity was maintained when selection of T cells from the memory pool into the recall response was examined. This preservation of diversity suggests this selection process may be an effective strategy for enabling immune control and subsequent protection as well as maintaining the ability to respond to viral escape mutants. Overall, the findings in this thesis expanded our understanding of the factors that determine the size and TCR complexity of the responding CD8+ T cell immune response to acute viral infection. It is only through the increase in knowledge of the process by which CD8+ T cell immune responses are generated from the small numbers of naïve CD8+ T cells that can we improve the strategies for vaccine design and development of therapeutics that target CD8+ T cell mediated immunity for viruses and tumour immunotherapy.