Genetic determinants of "innate" T lymphocytes development and homeostasis

“先天”T 淋巴细胞发育和稳态的遗传决定因素

• 批准号: 10251641
• 负责人: Laurent Gapin
• 金额: $ 23.33万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10251641
• 关键词: Adaptive Immune System; Address; Affect; Age; Antigens; Candidate Disease Gene; Cell physiology; Cells; Chromosome Mapping; Data; Data Set; Development; Environmental Risk Factor; Female; Flow Cytometry; Frequencies; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genetic Variation; Genotype; Glycolipids; Health; Homeostasis; Human; Immune; Immune response; Individual; Inflammatory; Link; Major Histocompatibility Complex; Maps; Measurement; Molecular; Mucous Membrane; Mus; Natural Immunity; Phenotype; Play; Population; Quantitative Trait Loci; Reproducibility; Resolution; Resource Development; Resources; Role; Source; Specificity; System; T-Cell Development; T-Lymphocyte; Testing; Therapeutic Uses; Thymus Gland; Variant; Vitamins; adaptive immunity; cell type; high dimensionality; immunoregulation; improved; latent infection; male; novel therapeutic intervention; response; sex; transcription factor; γδ T cells

Project Summary Innate conventional their requirement namely, molecules, the uncertain. systems, polymorphism mapping resources development a variation using T cells are a heterogeneous group of αβ and γδ T cells that respond much more r apidly than T cells upon activation. This swiftness of response r eflects their acquisition of functionality during development in the thymus. These innate T cells also share a non-MHC class I or II restriction for antigen recognition. Three major populations within the innate T cell group are recognized, the invariant NKT cells that recognize glycolipid antigens presented by non-polymorphic CD1d the mucosal associated invariant T (MAIT) cells t hat recognize vitamin metabolites presented by non-polymorphic MR1 molecules, and the gamma delta T cells which antigen specificities remain Altogether, these innate T cells, acting as bridges between the innate and adaptive immune contribute greatly to immune regulation and host protection. To appreciate the role that host play in steady-state evelopment and homeostasis of innate T cells, we propose to use QTL in the Collaborative Cross and Diversity Outbred (DO) mice. These genetically diverse mouse provide powerful experimental systems to test the ypothesis that variation in innate T cell and homeostasis is genetically regulated and to map the source of the diversity. We will conduct comprehensive screen of CC and DO strains for innate T cells to estimate the diversity resulting from genetic (Aim 1). We will then identify genes that underlie variation in innate T cell development/homeostasis QTL mapping (Aim 2). d h Given their capacity to link key inflammatory axes of innate and adaptive immunity, a better understanding of the molecular basis underpinning innate T cell development and plasticity, and how much this feature accounts for their pathophysiological roles, is critical for developing novel therapeutic approaches.

项目摘要 先天 常规 他们的 要求 也就是说， 分子， 的 不确定 系统， 多态性 映射 资源 发展 一 变化 使用 T细胞是αβ和γδ T细胞的异质性群体，其响应比 T细胞活化后。这种反应的敏捷性反映了他们在 胸腺中的发育。这些先天性T细胞也共享非MHC I类或II类限制 用于抗原识别。先天性T细胞群中的三个主要群体被识别， 识别由非多态性CD 1d呈递的糖脂抗原的不变NKT细胞 粘膜相关不变T（MAIT）细胞不能识别由 非多态性MR 1分子，以及保留抗原特异性的γ δ T细胞 总之，这些先天性T细胞，作为先天性和适应性免疫之间的桥梁， 有助于免疫调节和宿主保护。去欣赏主持人的角色 在先天性T细胞的稳态发育和稳态中发挥作用，我们建议使用QTL 协作杂交和多样性远交（DO）小鼠。这些基因多样的老鼠 提供了强有力的实验系统，以测试假设，先天性T细胞的变异， 和体内平衡是由基因调节的，并绘制多样性的来源。我们会进行 全面筛选CC和DO菌株的先天性T细胞，以估计遗传多样性导致的遗传多样性。 (Aim 1）。然后，我们将确定先天性T细胞发育/稳态变异的基础基因 QTL作图（目的2）。 D H 鉴于它们能够将先天和适应性炎症的关键轴 免疫，更好地理解支持先天T细胞发育和可塑性的分子基础， 以及这种特征在多大程度上解释了它们的病理生理作用，对于开发新的 治疗方法。