Both MHC class la and class Ib-restricted CD8+ T cells have been shown to participate in the immune response against intracellular bacteria infection. The kinetics and effector functions elicited by MHC class la- restricted T cells are well documented, however, less is known about antigen presentation by MHC class Ib molecules and the functions of their cognate T cells. H2-M3 is an MHC class Ib molecule which presents bacterial N-formylated peptides to T cells. Recent studies by our lab have shown that MS-restricted CD8+ T cells play a significant and nonredundant role in Listeria monocytogenes (LM) infection that bridges innate and adaptive immunity. Moreover, MS-restricted T cells can also be elicited during infection with Mycobacterium tuberculosis (Mtb). The significance of non-M3 class Ib-restricted T cells in bacterial infection remains to be defined. To investigate the unique early kinetics of MS-restricted T cells, we examined the development and function of these cells in TCR transgenic mice which express a TCR specific for M3/Listeria peptide complexes. We found that MS-restricted T cells can be positively selected by both hematopoietic cells and thymic epithelial cells, and that these two populations of MS-restricted T cells display different activation phenotypes. The objectives of this proposal are to determine how these distinct routes of selection contribute to the unique phenotype and function of MS-restricted T cells, and to determine the contribution of other non-M3 class Ib molecules to anti-microbial immunity. First, we will generate mixed bone marrow chimeras to elucidate which hematopoietic cells can select MS-restricted T cells. We will also compare the kinetics, effector functions, and memory phenotype of MS-restricted T cells selected by hematopoietic cells to those selected by thymic epithelial cells in the context of LM infection. Second, we will determine the kinetics and contribution of M3- and non-M3 class Ib-restricted T cell responses in LM and Mtb infection using class la-deficient and class la/MS-deficient mice. Finally, we will extend our study to identify other class Ib molecules which can present bacterial antigens through the generation of non-M3 class Ib-restricted T cell lines. Our studies on this relatively uncharacterized segment of the mammalian immunologic repertoire may lead to novel targets/methods for vaccination against infectious diseases.
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