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Title: Programming CD8 T cell memory development and protective immunity
Author: Yu-Lin, Teoh
ISNI:       0000 0001 3576 093X
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2007
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In order to elicit the ideal set of memory CD8 T cells, rational vaccine design and planning for vaccination regimes require additional knowledge on factors which affect CD8 memory development. Together with the initial conditions under which priming occurs, aspects upstream of the CD8 response such as antigen processing, trafficking and presentation have the ability to influence both the development of the response as well as the type of memory population generated. The exceptional influence of these factors on the resultant CD8 T cell response has led to the concept of CD8 T cell programming, highlighting the potential to manipulate CD8 T cell memory development by simply modifying priming strategies. The work presented in this thesis examines the development of CD8 responses under different conditions of priming and antigen presentation and attempts to provide evidence of a correlation between primary response traits and the outcome of an immune response in terms of protective immunity. As the investigation of early CD8 T cell activation events is naturally impeded by the limitation of precursor frequency, studies were conducted using the F5 TCR transgenic (influenza nucleoprotein; NP) murine model in conjunction with recombinant viral vectors engineered to express the influenza nucleoprotein (NP)antigen (Chapter 3: Groundwork). Differences between primary CD8 T cell responses elicited against vaccinia virus (VV) and modified vaccinia Ankara virus (MYA) were assessed and parameters' such as the rate of activation, degree of recruitment, expansion-contraction kinetics as well as the rate of memory marker acquisition compared (Chapter 4: Vector Comparison). Although MYA was demonstrated to be less immunogenic than VV, inducing. less robust primary responses, antigen-specific CD8 T cells activated by MYA appeared to develop better effector and memory qualities. The profiles of CD8 T cell development induced by the administration of a single viral vector (VV) via two different routes were also investigated (Chapter 5: Effect of Infection Route). Systemic VV infection via Lv. resulted in the generation of CD8 responses that focused more strongly against recombinant inserted antigen than the viral vector and provided greater protection against a secondary challenge with influenza virus. Taken together, results from these chapters indicated that a larger memory population does not necessarily imply better protective immunity. Enhanced primary response traits such as speed, magnitude and degree of activation or CD8 T cell recruitment into response during priming, generally assumed to be desirable in a vaccination setting, were also found to have little correlation with degree of protection. Instead, effector function and recall capacity proved to correlate best with challenge resistance and may be useful in assessing the potential of new vaccine candidates for clinical trials. Finally, the impact of antigen and APC trafficking on CD8 responses was investigated (Chapter 6: Role of CAMs on the development of CD8 T cell responses) and cell-adhesion molecules were shown to play an important role in the initiation ofCD8 responses.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available