The fundamental role of the immune system is to detect self from non-self. The detection and elimination of microbial infection is critical for human survival. One challenge to the immune system is infection from an intracellular microbe because the microbe masks its presence in a host cell. One strategy of the immune system to detect microbes is the sampling of different kinds of antigens, such as peptides, lipids and glycolipids, by antigen presenting molecules. A fundamentally unique arm of the immune system is MR1, which is an antigen presenting molecule that is intracellular, ubiquitously expressed across tissues, and detects small molecules derived from microbial metabolism. These features suggest that MR1 is poised to detect intracellular microbes. MR1 presents antigens to MR1-restricted T cells. These T cells are highly prevalent in the lungs and have the ability to kill infected cells. Because MR1 presents small molecule antigens and adopts an intracellular distribution, the mechanisms governing MR1 sampling of the intracellular environment are distinct from other antigen presenting molecules. Our hypothesis is that endosomal recycling and endosomal calcium signaling are key for MR1-dependent antigen presentation, and that these features distinguish MR1 from MHC- Ia antigen presentation. We use Mycobacterium tuberculosis (Mtb) as a model for intracellular infection and have identified calcium-sensitive trafficking proteins and calcium channels important for MR1 antigen presentation.
In Aim 1, we will define the role of the endosomal trafficking protein Syntaxin 16 in MR1- dependent antigen presentation.
In Aim 2, we will define the role of calcium sensitive Synaptotagmins in MR1- dependent antigen presentation.
In Aim 3, we will identify the important calcium channels involved in this process and examined the role of Two-pore channels. This research plan is part of a detailed training and career development plan for the applicant. In addition to hands-on basic science research with an emphasis on techniques such as measurement of intracellular calcium and live-cell fluorescence microscopy, the applicant will complete coursework in scientific writing and biostatistics to expand scientific knowledge and will attend scientific conferences to develop collaborations. Acquisition of all of these skills will lead to expertise in defining intracellular signaling cascades in antigen presenting cells, with the goal of obtaining an R01 by the end of the K08 award. The primary mentor has a long track record of training scientists and a Mentoring Committee will track the applicant's progress and contribute to the applicant's development as a scientist. Finally, the sponsoring institution, Oregon Health & Science University, has all the facilities and support necessary to support the proposal.
The antigen presenting molecule MR1 is fundamentally different than any other antigen presenting molecule in the human immune system. It is ubiquitously expressed in tissues, including the lungs, and is poised to rapidly detect intracellular infection. A better understanding of how MR1 presents antigens from Mycobacterium tuberculosis will be critical to the development of future MR1 based therapies against the disease.
