Cell Type-Specific Roles of TLR Signaling In Immune Responses

TLR 信号传导在免疫反应中的细胞类型特异性作用

• 批准号: 7370266
• 负责人: Anthony L Defranco
• 金额: $ 38.56万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7370266
• 关键词: Ablation; Alleles; Antibodies; Antibody Formation; Antigens; B-Lymphocytes; Bacteria; Bacterial Infections; CD4 Positive T Lymphocytes; Cell Maturation; Cells; Cellular Immunity; Dendritic Cells; Development; Disease; Elements; Endothelial Cells; Engineering; Epithelial Cells; Event; Exons; Genes; Genetic Recombination; Germ Lines; Goals; Gram-Positive Bacterial Infections; Growth; Helper-Inducer T-Lymphocyte; ITGAX gene; Immature Mast Cell; Immune; Immune response; Infection; Inflammation; Inflammatory; Introns; Language; Ligands; Listeria monocytogenes; Mediating; Mus; Natural Immunity; Nature; Ovalbumin; Patients; Phagocytes; Play; Production; Proteins; Receptor Signaling; Relative (related person); Role; Side; Signal Transduction; Site; Staphylococcus aureus; System; T-Lymphocyte; TNFSF5 gene; Testing; Thinking; Tissues; Toll-like receptors; Transgenes; Transgenic Organisms; base; cell type; cytokine; extracellular; improved; interest; killings; macrophage; mast cell; memory CD4 T lymphocyte; microbial; neutrophil; novel strategies; pathogen; receptor; recombinase; research study; response; sensor; vaccination strategy; Ablation; Alleles; Antibodies; Antibody Formation; Antigens; B-Lymphocytes; Bacteria; Bacterial Infections; CD4 Positive T Lymphocytes; Cell Maturation; Cells; Cellular Immunity; Dendritic Cells; Development; Disease; Elements; Endothelial Cells; Engineering; Epithelial Cells; Event; Exons; Genes; Genetic Recombination; Germ Lines; Goals; Gram-Positive Bacterial Infections; Growth; Helper-Inducer T-Lymphocyte; ITGAX gene; Immature Mast Cell; Immune; Immune response; Infection; Inflammation; Inflammatory; Introns; Language; Ligands; Listeria monocytogenes; Mediating; Mus; Natural Immunity; Nature; Ovalbumin; Patients; Phagocytes; Play; Production; Proteins; Receptor Signaling; Relative (related person); Role; Side; Signal Transduction; Site; Staphylococcus aureus; System; T-Lymphocyte; TNFSF5 gene; Testing; Thinking; Tissues; Toll-like receptors; Transgenes; Transgenic Organisms; base; cell type; cytokine; extracellular; improved; interest; killings; macrophage; mast cell; memory CD4 T lymphocyte; microbial; neutrophil; novel strategies; pathogen; receptor; recombinase; research study; response; sensor; vaccination strategy

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.

描述（由申请人提供）：近年来，Toll样受体（TLR）已成为先天免疫的关键识别要素，既可以在感染部位诱导炎症，又是诱导适应性免疫反应。这些受体在许多组织，未成熟的树突状细胞，组织巨噬细胞和肥大细胞以及其他几种细胞的三种主要类型的免疫细胞上表达。在拟议的项目中，我们将定义哪种类型的细胞负责介导基于TLR的免疫反应。在这些研究中，我们将利用有条件的等位基因，用于将键TLR信号适配器分子MyD88设计到小鼠生殖系中。在这个等位基因中，我们将LOXP位点放在MyD88基因必需外显子3的任一侧的内含子中，结果是细胞中的CRE表达将导致外显子3的删除和MyD88基因失活。 MyD88的条件等位基因将与在树突状细胞（CD11C-CRE）中有选择地表达CRE的转基因一起使用，在巨噬细胞和中性粒细胞（Lysm-Cre）中有选择地使用，或在B细胞中选择性地表达CRE（CD19-CRE）。然后，将测试这些小鼠在特定细胞类型中丧失MyD88的影响：诱导效应子和记忆CD4 T细胞反应（AIM 1），炎症的诱导以及两种革兰氏阳性细菌病原体的生长限制，李斯特菌单核细胞增生李斯特菌单核细胞增多菌和葡萄球菌aureus aureus 2（aim 2），以及抗体的养殖类（AIR 2），以及Antibien的养生。这些研究将定义TLR信号传导在树突状细胞，巨噬细胞，肥大细胞和B细胞中的作用，以诱导炎症并促进有效的适应性免疫反应。 叙述性语言摘要：拟议的研究将确定组织中哪些免疫细胞负责对细菌感染的各种免疫反应，包括炎症，细胞介导的免疫和特定抗体的产生。这将通过使用转基因小鼠来实现，其中关键免疫细胞类型无法识别细菌的存在。这些研究将有助于改善疫苗接种策略和制定新的策略来阻止炎症性疾病患者的炎症。