Tuberculosis (TB) is a leading cause of infectious disease mortality worldwide, accounting for 10.4 million new cases and 1.3 million deaths annually. An understanding of the immune response to Mtb is of central importance in the development of improved vaccines. In this regard our laboratory, under the auspices of the VA Merit Program, has defined Mucosal Associated Invariant T (MAIT) cells as a class of cells that are restricted by the highly conserved MR1 molecule, recognize Mtb-infected cells, have effector capacity in the thymus and cord blood, yet display evidence for memory following exposure to Mtb, and are enriched in the lungs. MAIT cells are found in tissues such as the lung and intestine. Because MAIT cells recognize small molecules, such as metabolites of riboflavin, we postulate that the cell surface expression of MR1 is tightly regulated to avoid activation of these cells in the absence of intracellular infection. Indeed, with the support of the VA Merit Program, we have found that MR1 is both located in an endosome, requires a ligand for translocation to the cell surface, and is dependent on vesicular trafficking for the presentation of Mtb-derived antigens to MR1T cells. Furthermore, we find that the mechanisms underlying presentation of Mtb-derived antigens can be distinguished from antigens that are exogenously delivered, suggesting that there are specialized mechanisms for sampling the intracellular environment. Therefore, in this application we will focus on defining the molecular mechanisms that allow for the appropriate presentation of intracellular infection, with a focus on Mtb. We will 1) Define the molecular chaperones required for the presentation of microbials ligands, and 2) Define the role of MR1 SNPs and splice variants in controlling the recognition of the Mtb infected cell, and will evaluate these variants in clinically relevant outcomes following exposure to Mtb. This project contains two Aims:
AIM 1 : Define the molecular chaperones necessary for the presentation of Mtb-derived ligands 1a. Determine the molecular chaperones associated with MR1. 1b. Determine the role of riboflavin transporters in the uptake or trafficking of MR1 ligands.
AIM 2 : Define the role of MR1 SNPs and splice variants in human susceptibility to TB 2a. Determine the relationship of MR1 SNPs and splice variants and clinical outcomes associated with exposure to Mtb. 2b. Determine the functional significance of MR1 SNPs. 2c. Determine the relationship of MR1 splice variant expression and the capacity of cells to present MR1 ligands to MR1T cells.
Tuberculosis remains an important cause of infectious disease morbidity and mortality worldwide, and remains a problem of particular concern to those in the armed forces. The organism that causes tuberculosis, Mycobacterium tuberculosis, is an intracellular pathogen such that improved definition of those mechanisms by which the immune system recognizes intracellular infection provides direct application to improved vaccines and diagnostics. This application is focused on understanding how a unique population of innate human CD8+ T cells identify those cells containing Mtb.
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