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 production and 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.
