Current and Past Research Programs
Tuberculosis, caused by the bacterium Mycobacterium tuberculosis (Mtb), remains a leading cause of death worldwide (WHO). Developing improved vaccines for Mtb will require a better understanding of early Mtb-specific cellular responses that are critical to controlling infection. Mtb is a facultative intracellular pathogen, taken up by macrophages, dendritic cells, and epithelial cells in the lung. Epithelial cells are poised to play a critical role in early control of Mtb infection, as they are likely the first cells encountered by Mtb. While many studies have addressed the role that phagocytic cells play in control of Mtb infection, little is known about the role epithelial cells play in either the innate or adaptive immune response to Mtb. Epithelial cells lack MHC-II and hence the ability to stimulate CD4+ T cells. Consequently, recognition of infected epithelial cells is dependent on CD8+ T cells. These cells are uniquely able to recognize intracellular infection and thus may play an important role in the host response to infection with Mtb. Early detection of Mtb within the lung epithelium could contribute to successful containment of Mtb in two ways: First, through containment of Mtb and elimination of infected cells, or second, by priming the adaptive immune response. In general, my research is focused on characterizing the events leading to the early activation of innate CD8+ T cells, such as recognition of an infected epithelial cell.
Specifically, I am pursuing an understanding of the mechanisms by which Mtb antigens are processed and presented on non-classical Class I molecules by epithelial cells to innate CD8+ T cells. Our laboratory has recently identified a new subset of Mtb-reactive CD8+ T cells present in lungs of uninfected people, as well as those with latent infection (LTBI) and active disease. These Mtb-reactive cells, known as mucosa-associated invariant T cells (MAITs), are restricted by the HLA-Ib molecule, MR1 (MHCI-related protein), and can recognize Mtb-infected antigen presenting cells (APCs) – both monocyte-derived cells, such as dendritic cells (DC) and macrophages, and epithelial cells. The mechanism by which MR1 encounters and is loaded with Mtb antigen in epithelial cells is unknown. With other Class I and Class II molecules, the cellular localization of the MHC molecule and the antigen determines the pathway by which the antigen becomes loaded. Currently, we are defining the epithelial cell niche where Mtb resides, and characterizing how this intracellular compartment matures after infection. In addition, we are identifying the intracellular trafficking pathways involved in loading of Mtb antigens on MR1.