The role of regulatory T cells in M. tuberculosis infection

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DESCRIPTION (provided by applicant): Mounting evidence indicates that Tregs play a critical role in preventing autoimmunity, inhibiting transplant graft rejection, suppressing immune response to tumors and to microbial pathogens. However limited information is available about the role of Tregs in infection due to M. tuberculosis, a pathogen that causes tremendous morbidity and mortality world-wide. Recently, we found that, in healthy tuberculin reactors, T-cells enhance production of prostaglandin E2 (PGE2) by monocytes, and PGE2 favors expansion of Tregs. In addition, NK cells inhibit Treg expansion in response to M. tuberculosis by direct lysis of Tregs. This proposal will characterize the mechanisms by which macrophages and NK cells affect expansion of Tregs in healthy tuberculin reactors through the following aims. 1) Determine the cellular mechanisms by which M. tuberculosis-infected monocytes expand Tregs. We will identify the soluble T cell factors and the factors mediating T-cell:monocyte cell-to-cell contact that increase PGE2 productionand expand Tregs in response to M. tuberculosis infection. The monocyte subpopulation that favors Treg expansion will also be identified. 2) Determine the mechanisms by which NK cells inhibit expansion of Tregs, focusing on mechanisms by which NK cells lyse Tregs. These studies will provide an improved understanding of the mechanisms that mediate Treg expansion in the response to intracellular bacterial infection. The information gained will help us to design more effective antituberculosis vaccines, and to lay the groundwork for developing immunotherapeutic strategies based on inhibiting Treg development.Tuberculosis is a leading cause of death from infectious agents, claiming 1.9 million lives worldwide annually. Most persons who are infected with Mycobacterium tuberculosis remain healthy and have protective immunity, but 10% of infected individuals develop primary tuberculosis soon after infection or reactivation tuberculosis many years later. Understanding the factors that regulate protective immune responses against M. tuberculosis is essential for development of an effective vaccine. Recently, attention has been focused on regulatory CD4+ T-cells (Tregs), which are known to dampen the immune response to different infectious agents. However, limited information is available on the capacity of these organisms to expand Tregs in human infection. In this proposal, we will determine the cellular mechanisms involved in Treg expansion, information which will lay the foundation for development of Treg-based therapy to reduce tissue damage from an overactive immune system. These studies will also yield clues to the mechanisms that may underlie reactivation of tuberculosis in some individuals. We will also determine the mechanism by which natural killer cells, a special type of blood cell, destroy Tregs and therefore inhibit Treg expansion, a possibility that has not been previously explored. These studies will provide fundamental information on the immune response to M.tuberculosis and other bacteria. They will facilitate development of strategies to strengthen the immune response, thereby preventing and treating tuberculosis and other infections, particularly in immunocompromised persons with defective immunity.