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Title: Molecular profiling CD8+ T-cell memory inflation
Author: Sims, Stuart
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2013
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Infection with murine cytomegalovirus (MCMV) induces a large population of virus-specific CD8+ T-cells that is maintained at a high frequency in the peripheral organs for the lifetime of the host. This striking response to MCMV is termed "memory inflation". It has also been shown that a similar response occurs after immunization with a non-replicating adenovirus expressing a transgene. The key features which distinguish "inflating" CD8+ T-cell memory responses from classical "non-inflating" CD8+ T-cell memory responses have not been fully defined. To determine the molecular signature of memory inflation I sorted antigen-specific cells ex vivo and compared the gene expression profiles of inflationary CD8+ T-cells to those of central memory and effector CD8+ T-cells. This data showed that memory inflation has a distinct expression profile, with high expression of KLR receptors, specific chemokine receptors such as CX3CR1, transcription factors such as T-bet and Foxk1, and survival factors, such as Bcl-XL and down regulation of inhibitory molecules such as BTLA. These inflationary cells are functional - expressing an array of cytokines, granzymes, IFN&gama;, and TNFα, and lack transcriptional features of T-cell exhaustion. Similar features were identified in CD8+ T-cells undergoing memory inflation using both the MCMV and adenovirus models. To address the turnover of these "inflationary" CD8+ T cells and their role in vivo, I created tetramers bound to the toxin saporin to specifically knock out inflationary cells. I found that they contribute to the control of viral replication, since depletion was followed by a rise in viral load and a subsequent rebound increase in the tetramer+ population. In the final chapter I addressed the role of one specific cell surface molecule, CD73, during CD8+ T-cell memory. I found that although CD73 is thought to play a role in immune regulation, CD73-/- mice showed normal memory inflation and classical non-inflationary memory development. Overall the data in this thesis define for the first time the transcriptional profile associated with CD8+ T-cell memory and show the distinct nature of this T-cell programme in vivo. Future work using further genetically modified mouse strains should allow definition of the critical molecules and pathways involved in the development of these important memory pools.
Supervisor: Klenerman, Paul Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Immunology ; Biology ; Viruses