Function and regulation of CD8 T cells during <i>Mycobacterium tuberculosis</i> infection in a murine model
Although more doses have been given of the tuberculosis vaccine (BCG) than any other vaccine in history, tuberculosis remains the second leading cause of death due to an infectious agent worldwide. Our understanding of the immune response to the bacterium is incomplete, which has partly been due to a lack of known bacterial T cell epitopes. In recent years, several epitopes have been identified, which has enabled the use of new reagents and assays to study T cell responses. Furthermore, development of recombinant bacteria expressing model antigens has facilitated the use of many more reagents and techniques, as well as allowing us to compare M. tuberculosis -specific T cell responses to those induced by other infectious agents. The aim of this thesis was to better understand the CD8 T cell response to M. tuberculosis and identify factors that regulate the response. We showed that, unexpectedly, the primary CD8 T cell response was more effective than the memory CD8 T cell response to M. tuberculosis, in that primary cells secreted higher levels of IFN-γ and were more cytotoxic. We also showed that cytotoxicity and secretion of IFN-γ were carried out by distinct M. tuberculosis-specific CD8 T cells, which indicates that there is a functional defect in these cells that is not seen in other infections. Contrary to chronic viral infections, however, M. tuberculosis-specific CD8 T cells did not appear to become exhausted, despite the chronicity of the infection. We further showed that the function of CD8 T cells was influenced by various factors, such as interactions with pre-existing memory cells, the quality of CD4 T cell help and the environment that the cells were primed in. Manipulation of these factors can increase the quality of the immune response, giving multifunctional CD4 and CD8 T cells, as well as CD8 T cells capable of simultaneously being cytotoxic and secreting IFN-γ, without altering the bacterium. This indicates that modifications in delivery of tuberculosis vaccines may result in improved efficacy. The work presented may contribute to advances in the development of new tuberculosis vaccines, as well as improvement in efficacy of the existing vaccine.