Mycobacterium tuberculosis is the leading cause of death due to a single infectious agent worldwide. Immune response elicited against the bacterium is sufficient to control, but not to eliminate the pathogen leading to the establishment of asymptomatic state called latency. Currently very little is known about conditions that are required to prime robust, protective immune response in the initial stages of infection. We hypothesized that CD40 ligation is essential for the priming of strong Th1 response and for the subsequent control of M. tuberculosis infection. Furthermore, it is unknown how persistent exposure to mycobacterial antigens affects the functionality of T cells. Our initial thought was that the reason why immune response cannot eliminate M. tuberculosis and why reactivation occurs is due to T cell exhaustion as a result of continuous antigenic stimulation. Since the goal of every vaccine strategy is to elicit long-lasting and protective immunity, it is necessary to define the factors required for the development and maintenance of effector and memory T cell responses. We hypothesized that CD4 help and IL-15 are required for the development of functional CD8+ memory responses. Our results indicate that in murine model of tuberculosis CD40 ligation on antigen presenting cells either by host- or mycobacterium-derived ligands, is essential for the induction of robust IFN-× T cell response resulting in protection against disease and death. Once a strong immune response is elicited, long-term control of M. tuberculosis infection is mediated by dynamic changes in the frequency and types of T cell effector functions. We identified that IL-15 was not essential for the proliferation of CD4+ and CD8+ T cells or for the maintenance of their effector functions after primary and secondary M. tuberculosis infection. Our findings indicate that CD4 help was required during priming of effector CD8+ T cells and during secondary infection for the functional and durable memory CD8+ T cell responses. Collectively, the findings presented in this thesis broadened our understanding of what factors are essential for the generation and maintenance of functional effector and recall responses following M. tuberculosis infection.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-08182004-120735 |
| Date | 18 August 2004 |
| Creators | Lazarevic, Vanja |
| Contributors | Dr. Olivera Finn, Dr. Karen Norris, Dr. Robert Hendricks, Dr. Simon Barratt-Boyes, Dr. JoAnne Flynn |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-08182004-120735/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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