The mammalian immune response is an intricately regulated, dynamic process providing the host with protection from the vast number of pathogenic microorganisms. Herein, these studies identified the impacts of regulating host defense by immune suppressive mechanisms, following infection with the bacterial pathogen Listeria monocytogenes. These investigations identified that changes in the inflammatory signals present during Listeria infection resulted in drastically different outcomes in the priming of protective T cells, when these cells were stimulated by either the immune suppressive molcules Cytotoxic T Lymphocyte Antigen (CTLA)-4 or Program Death Ligand (PDL)-1.
Due to these findings, whereby changes in the immunologic environment altered the function of suppressive molecules, we examined whether physiologic changes in the immune system would impact host defense to infection. The natural expansion of the immune suppressive regulatory T cell (Tregs), while essential for sustaining pregnancy, resulted in increased maternal susceptibility to Listeria infection. Morevoer, Listeria entry into the host cell cytoplasmic compartment was suffient to reduce Treg suppressive potency and fracture Treg-mediated maternal tolerance. Lastly, we identified that the expansion of Tregs during pregnancy was primed by fetal-specific antigens and resulted in a long-lived population of cells, which provide "regulatory" memory. This is the first demonstration of Tregs with the ability to re-expand following a secondary antigen challenge (either fetal or pathogen-derived) and should spark future investigation into the role of regulatory memory.
University of Minnesota Ph.D. dissertation. June 2012. Major: Microbiology, Immunology and Cancer Biology. Advisor: Sing Sing Way M.D. Ph.D. 1 computer file (PDF); xi, 234 pages.
Rowe, Jared Hamilton.
Immune suppressive molecules and regulatory T cells control host defense against listeria monocytogenes infection.
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