The currently used TB vaccine, BCG, was first administered to people in 1921 and is currently one of the most widely used vaccines in the world. Unfortunately, it is not very effective; despite its widespread use approximately one-third of the world’s population is infected with the bacterium that causes tuberculosis, and nearly 2 million people die from TB every year. A new vaccine is urgently needed. The work of the Urdahl lab is based on the belief that the biggest barrier to developing a more effective vaccine is the lack of fundamental understanding of why the immune system often fails to eradicate the bacterium that causes TB and how these factors can be overcome to achieve better protection.
Although immune cells called T cells are clearly important for protection, their ability to eradicate Mtb has limitations. Many of these limitations stem from immune-dampening 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.
Above: Foxp3-expressing regulatory T cells in the lungs are depicted by green fluorescence
The Urdahl lab is interested in understanding the factors that impede T cell-mediated immune protection during persistent Mtb infection. Urdahl discovered that a subset of T cells with immune-dampening properties called regulatory T cells (T regs) restrict Mtb eradication. Furthermore, the lab found that Mtb readily induces T reg cells that are specific for the pathogen. These pathogen-specific T regs are extremely potent in restricting immunity by delaying the induction of effector T cells, the primary mediators of immune protection. The Urdahl lab believes the induction of these cells may represent a strategy by which Mtb thwarts the immune response to gain a foothold in the lung and establish a persistent infection. 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.
Urdahl is also interested in understanding T cell subsets that promote protection against tuberculosis. Using state-of-the-art tools to track T cells specific for Mtb antigens, the Urdahl lab will define unique subsets of T cells based on their functional capacities and determine the lineage relationships between these different cells. The Urdahl lab is investigating how genetic variation between individuals influences the relative numbers of T cells with different functional properties. 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.
- Regulatory T cells and tuberculosis
- Effector T cell subsets and tuberculosis
- Effects of exposure to environmental mycobacteria on subsequent immunity to Mtb
Urdahl’s work is supported by the National Institutes of Health and the Paul G. Allen Family Foundation.