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TCR signal strength and iNKT cell subset development

TCR 信号强度和 iNKT 细胞亚群发育

基本信息

批准号：
10219060
负责人：
Laurent Gapin
金额：
$ 38.1万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-10 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10219060
关键词：
Affect Affinity Antigenic Specificity Antigens Autoimmune Diseases Autoimmunity Avidity Biological CD1d antigen Cell Count Cell membrane Cell physiology Cells Communicable Diseases Complex Cues Cytoskeleton Cytotoxic T-Lymphocytes Data Defect Development Disease Resistance Event Exhibits Gene Expression Genetic Goals Health Homeostasis Human Immune Immune response Immunity Immunologics Infection Injury Knowledge Ligands Lipids MHC Class I Genes Major Histocompatibility Complex Malignant Neoplasms Metabolic Diseases Metabolism Mission Mouse Strains Mus Mutation Nature Perception Play Population Predisposition Pregnancy Process Protein Tyrosine Kinase Receptor Activation Receptor Signaling Regulation Research Role Sensitivity and Specificity Signal Transduction Signal Transduction Pathway Specific qualifier value T cell differentiation T cell therapy T-Cell Antigen Receptor Specificity T-Cell Development T-Cell Receptor T-Lymphocyte T-Lymphocyte Gene Rearrangement T-Lymphocyte Subsets Testing Therapeutic Therapeutic Uses Thymus Gland Tissue Preservation Tissues United States National Institutes of Health Wild Type Mouse Work ZAP-70 Gene base biophysical properties clinical application cytokine human disease immunological intervention immunoreaction immunoregulation improved in vivo innovation insight novel strategies pathogen prevent progenitor programs response

项目摘要

Project Summary Invariant Natural Killer T (iNKT) cells play a central role in several immune responses in diverse biological contexts ranging from autoimmunity, injury and infections to pregnancy and metabolic disease as well as cancer. iNKT cells are characterized by their use of a very limited T cell antigen receptor (TCR) repertoire to recognize lipid antigens presented by CD1d, a non-polymorphic major histocompatibility complex class I-like antigen-presenting molecule. A number of functionally distinct iNKT cell subpopulations, each with propensity to traffic to different tissues and to secrete different cytokines upon activation, have been defined. Although it is clear that these fate assignments are conferred upon iNKT cells during selection in the thymus, the environmental cues that direct these decisions are unknown. Our preliminary data show that 1) in wildtype mice, the avidity of the iNKT TCR correlates with iNKT cell subsets and the expression of markers reflecting strength of signaling during selection; 2) the development of iNKT cells in mice with a fixed TCR repertoire is affected similarly on different genetic backgrounds; 3) the V usage and CDR3 sequences are unique to each iNKT cell subset; 4) signaling and gene expression in the earliest definable stage of iNKT cell development, immediately after engagement of the TCR by natural ligands in vivo, is altered in mice with reduced TCR signaling. These mice also exhibit a cell intrinsic defect in development of iNKT cell subsets. Based on these preliminary studies, we hypothesize that iNKT cell differentiation and function is determined by TCR specificity and signal strength. This hypothesis will be tested by pursuing the following specific aims: 1) Determine the basis for strain differences in thymic iNKT subset composition; 2) Determine the effect of affinity and ligand- specificity of the TCR on development of iNKT cell subsets. The proposal is innovative because it directly explores the role of TCR specificity/affinity for self-ligands in specifying the development of iNKT cell subsets. The proposed research is significant because it will inform our understanding of iNKT cell subset development and dynamics, a pre-requisite to immune intervention aimed at manipulating and optimizing iNKT cell-based therapies.

项目总结