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Endothelial Regulation of T Cell Subset Migration

T 细胞亚群迁移的内皮调节

基本信息

批准号：
7753044
负责人：
ANDREW H LICHTMAN
金额：
$ 48.95万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7753044
关键词：
AKAP9 gene Address Adhesions Adhesives Affect Allografting Antibodies Antigens Autoimmune Diseases Autoimmune Process Automobile Driving Behavior Binding Blocking Antibodies Brain CD4 Positive T Lymphocytes CD47 gene CD8B1 gene Cell Adhesion Cell Adhesion Molecules Cell Communication Cells Characteristics Complex Cytokine Signaling Data Disease Disease model E-Selectin Endothelial Cells Endothelium Functional disorder Genes Goals Heart Helper-Inducer T-Lymphocyte Homing Immune System Diseases In Vitro Infection Infiltration Inflammation Inflammatory Integrins Interferons Interleukin-13 Interleukin-17 Interleukin-4 Interleukin-5 Interleukin-6 Intestines Islets of Langerhans Knock-out Knockout Mice Knowledge Label Learning Life Ligands Link Mediating Methods Microbe Modeling Molecular Mus Organ P-Selectin Pathologic Pathology Pathway interactions Peritoneum Phase Phenotype Physiological Play Population Principal Investigator Process Proteins Publishing Recombinants Recruitment Activity Regulation Relative (related person)Research Design Role STAT3 gene Selectins Signal Transduction Site Skin T-Lymphocyte T-Lymphocyte Subsets Techniques Testing Th1 Cells Th2 Cells Tissues Transduction Gene Transgenic Mice Transgenic Organisms Vascular Endothelial Cell Viral Work base cell motility cell type chemokine chemokine receptor cytokine in vivo interleukin-22 interleukin-23 intravital microscopy mRNA Expression microbial migration neutrophil programs research study response small hairpin RNA therapeutic target transcription factor

项目摘要

Different T cell subsets are defined on the basis of the cytokines they produce, and they perform distinct protective and pathologic roles. Migration of effector T lymphocytes into tissues is regulated by molecular interactions of the T cells with vascular endothelial cells (EC). The chemokine receptors and adhesion molecules characteristic of each T cell subset play essential roles in determining how that subset migrates into tissues and contributes to disease. Thi and Th2 helper T cell subsets, discovered over 20 years ago, secrete interferon y or IL-4, IL-5 and IL-13, respectively. Recently, a third major helper T cell subset called Th17 has been identified. Th17 cells secrete IL-17 and IL-22, and contribute in significant ways to the pathology of organ specific autoimmune diseases, as well as to protective responses against certain microbial infections. There is substantial evidence that CDS"^ T cells can differentiate into IL-17 producing (Tc17) cells as well. The mechanisms of migration of IL-17 producing CD4* and CD8+ (Type 17) T cells into inflammatory sites are largely unexplored relative to interferon-y producing Thi and Tc1 (Type 1) T cells. Our preliminary data indicate that Th17 cells engage in adhesive interactions with selectins, integrins, and EC, and that there are significant differences in the migratory phenotypes of Type 17 and Type 1 cells. In this proposal, we will study EC interactions and migration of Type 17 T cells. The experimental program includes three Specific Aims. In Aim 1, we will determine the distinguishing features of Type 17 vs. Type 1 interactions with EC, which contribute to temporal or spatial subset specific recruitment and to the association of neutrophilic inflammation with Thi7 cells. We hypothesize that recruitment of one subset will impact on the selectivity of subsequent T cell recruitment. We will also explore if Type 17, but not Type 1 effector T cell recruitment is coordinately regulated with neutrophilic infiltration. The experimental approach will include analyses of protein and mRNA expression of relevant molecules in primary mouse Thi7 and Tcl7 cells and studies of T cell interactions with recombinant adhesion molecules and with endothelium in vitro under physiological flow conditions. Aim 2 will focus on the molecular signals needed for the acquisition of the selectin-binding phenotype of Type 17 cells, and comparisons will be made with the different signals required selectin ligand expression in Type 1 T cells. The experimental approach will involve analysis of different cytokine signals and downstream transcription factors linked to expression of selectin ligands, with a particular focus on the contrasting roles of RORyT and Tbet, which are the signature transcriptional regulators of Th17 and Th1 cells. Aim 3 will compare the recruitment of Type 17 and Type 1 effector T cells in vivo. The experimental approach will include transfer of distinctly labeled Thi7, Tcl7, Th1 and Tc1 populations into different mouse inflammatory models. The migratory behavior of the Type 17 and Type 1 T cells in the host mice will be assessed by several quantitative techniques. The adhesion pathways and chemokines identified in Aim 1 will be evaluated in these models using antibody blocking and T cells or host mice genetically deficient in adhesion molecules and chemokine receptors. Collaborative studies with Projects 1 and 3 will focus on CD47- and integrin-dependent mechanisms of Th17- and Tc17-endothelial interactions. The information obtained from these studies will be essential for a full understanding the important recruitment phase of T cell-mediated diseases, and the data will help determine therapeutic targets that are T cell subset specific.

不同的T细胞亚群是根据它们产生的细胞因子来定义的，它们具有不同的保护和病理作用。效应T淋巴细胞向组织的迁移受T细胞与血管内皮细胞（EC）分子相互作用的调节。趋化因子受体和每个T细胞亚群的粘附分子特征在决定该亚群如何迁移到