Cell Type-Specific Roles of TLR Signaling In Immune Responses

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DESCRIPTION (provided by applicant): In recent years, Toll-like receptors (TLRs) have emerged as critical recognition elements of innate immunity, both for induction of inflammation at the site of an infection and for induction of an adaptive immune response. These receptors are expressed on the three major types of immune cells in many tissues, immature dendritic cells, tissue macrophages, and mast cells, as well as on several other types of cells. In the proposed project, we shall define which type of cell is responsible for mediating TLR-based immune responses. In these studies, we shall take advantage of a conditional allele we have engineered into the mouse germ line for the key TLR signaling adaptor molecule MyD88. In this allele, we have placed loxP sites in the introns on either side of the essential exon 3 of the myd88 gene, with the result that Cre expression in a cell will result in deletion of exon 3 and inactivation of the myd88 gene. This conditional allele of myd88 will be used together with transgenes that express Cre either selectively in dendritic cells (CD11c-Cre), selectively in macrophages and neutrophils (LysM-Cre), or selectively in B cells (CD19-Cre). These mice will then be tested for the effect of loss of MyD88 in particular cell types for: induction of effector and memory CD4 T cell responses (Aim 1), induction of inflammation and restriction of growth of two gram-positive bacterial pathogens, Listeria monocytogenes and Staphylococcus aureus (Aim 2), and for promotion of antibody responses to protein antigens (Aim 3). These studies will define the roles of TLR signaling in dendritic cells, macrophages, mast cells, and B cells for induction of inflammation and for promotion of effective adaptive immune responses. Narrative Lay Language Summary: The proposed studies will determine which immune cells in tissues are responsible for initiating various immune responses to bacterial infection, including inflammation, cell-mediated immunity, and production of specific antibodies. This will be accomplished by the use of genetically modified mice, in which key immune cell types are unable to recognize the presence of bacteria. These studies will be useful for improving vaccination strategies and for developing novel strategies to block inflammation for patients with inflammatory diseases.