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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: 2012
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Infection with murine cytomegalovirus (MCMV) induces a large population of virusspecific CDS· 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-repl icating adenovirus expressing a transgene. The key features which distinguish "infiating" CDS· T-cell memory responses from classica l "non-infiating" CDS· T-cell memory responses have not been fully defined. To determine the molecular signature of memory inflation I sorted antigen-specific ce lls ex vivo and compared the gene expression profiles of infiationary CDS· T-cells to those of central memory and effector CDS+ 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 regu lation of inhibitory molecules such as BTLA. These inflationary cells are functional - expressing an array of cytokines, granzymes, IFNy, and TNFa, and lack transcriptional features of T-cell exhaustion. Similar features were identified in CDS· T-cells undergoing memory inflation using both the MCMV and adenovirus models. To address the turnover of these "inflationary" CDS+ T ce lls 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 vira l repl ication, since depletion was followed by a rise in viral load and a subsequent rebound increase in the tetrarner+ popul ation. In the final chapter I addressed the ro le of one specific cel l surface molecule, CD73, during CDS· T-cell memory. I found that although CD73 is thought to playa role in immune regu lation, CD73-1 - mice showed normal memory inflation and class ical noninflationary memory development. Overall the data in this thesis define for the first time the transcriptional profile associated with CDS· 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: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available