Over one-third of the world's population is infected with Mycobacterium tuberculosis causing two million deaths every year. Clinically, only 5-10% of M. tuberculosis infected people go on to develop the disease tuberculosis signifying that most infected individuals develop long-lived protective immunity. Cellular immunity to M. tuberculosis plays a critical role in controlling infection and an effective T cell response determines whether the infection resolves or develops into clinically evident disease. A culmination of many studies has led to the appreciation that class I MHC-restricted CD8⁺ T cells are required for optimum immunity to M. tuberculosis. However, little is know about the development and function of these cells in a protective immune response.

This dissertation focuses on defining the development and function of protective CD8⁺ T cells in immunity to M. tuberculosis infection in the mouse model system. The studies presented take advantage of newly defined antigenic peptides that can be used to specifically address these questions. Investigating the development of CD8⁺ T cells, we find that infection of animals with bacteria that cannot secrete a specific protein antigen abrogates the generation a CD8⁺ T cell response to that antigen. Therefore priming of M. tuberculosis -specific CD8⁺ T cells requires bacterial secretion of the target antigen.

During chronic disease, we find that a subset of these M. tuberculosis -specific CD8⁺ T cells become bona fide memory cells that acquire a central memory phenotype, persist following chemotherapeutic resolution of infection, and functionally expand upon secondary challenge. In all the inbred strains we analyzed, M. tuberculosis-specific CD8⁺ T cells elicited by infection are cytolytic towards targets in vivo. Furthermore, these cells are able to use several mechanisms of killing in vivo, including perforin-mediated killing. Importantly, protection afforded by transfer of immune CD8⁺ T cells was perforin dependent. Finally, we present a unique demonstration that vaccine elicited M. tuberculosis-specific CD8⁺ T cells, per se, can protect from infection in a prophylactic manner. Taken together, these studies progress our understanding of the endogenous protective CD8⁺ T cell mediated immune response to M. tuberculosis and can provide insights into the development of new and improved tuberculosis vaccines.