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Despite efforts to prevent Mycobacterium tuberculosis (Mtb) infection through widespread immunization with the BCG vaccine, tuberculosis remains one of the leading infectious killers worldwide. The development of an efficacious vaccine is hampered by our poor understanding of the fundamental reasons why Mtb persists in the host in the face of an apparently robust immune response. Although T cells, especially IFN-y-producing CD4+ T cells, are clearly important for protection, their ability to eradicate Mtb is subject to limitations. Many of these limitations stem from immunosuppressive mechanisms that protect host tissue from collateral damage caused by an excessive inflammatory response to infection. Whether this immune response can be shifted to achieve enhanced protection without harming the host will require greater understanding of both the immune protective and suppressive factors involved.
The Urdahl lab is interested in understanding the factors that impede T cell-mediated immune protection during persistent Mtb infection. We have recently discovered that Foxp3-expressing regulatory T cells (T regs) restrict Mtb eradication, and pathogen-specific T regs are extremely potent in mediating this activity. Even small numbers of Mtb-specific T regs delay the arrival of effector T cells in the lung, the primary site of Mtb infection, and cause an increased bacterial burden. Future research will seek to elucidate how Mtb-specific T regs are induced and to define their precise roles and activities at different stages of infection. A key question that drives these studies is whether T reg function can be safely manipulated to prevent or treat tuberculosis.
We are also interested in understanding T cell subsets that promote protection against tuberculosis. Using MHC class I and II tetramers, we can monitor the function of Mtb-specific CD8+ and CD4+ T cells throughout the course of infection. We seek to determine the lineage relationships between Mtb-specific T cells with different functional capacities, including proliferation, IFN-y production, IL-17 production, and Foxp3 expression. We plan to investigate how variations in innate immune responses help shape the subsequent T cell responses to Mtb. These studies will provide insights into how long-lived populations of protective T cell subsets are induced and maintained during persistent Mtb infection, and should help to inform novel immunization strategies.
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Fred Hutch | University of Washington
Institute for Systems Biology (ISB)| Center for Infectious Disease Research