Transcriptional Regulation of Innate T cell fate

先天 T 细胞命运的转录调控

• 批准号: 10283893
• 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: 2021-07-14 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10283893
• 关键词: Adaptive Immune System; Allergic; Animal Model; Antigen-Presenting Cells; Antigens; Autoimmunity; Bacteria; Bee Venoms; CD1 Antigens; CD3 Antigens; Cell Lineage; Cells; Chromatin; Collection; Cytotoxic T-Lymphocytes; Data; Development; Disease; Epigenetic Process; Event; Exposure to; Family; Family member; Genetic Transcription; Glycolipids; Health; Human; Immune; Immune response; Immunity; In Vitro; Inflammatory; Instruction; Joints; Knowledge; Lead; Link; Mediating; Molecular; Mucous Membrane; Mus; Mycobacterium tuberculosis; Natural Immunity; Output; Peripheral; Population; Process; RNA; Receptor Activation; Receptor Signaling; Resolution; Rhus radicans; Role; SLAM protein; Shapes; Signal Transduction; Snake Venoms; Specificity; System; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic Intervention; Therapeutic Uses; Thymus Gland; Tissues; Transcriptional Regulation; Virus; Vitamins; ZNF145 gene; adaptive immunity; consumer product; cytokine; epigenetic regulation; epigenome; human disease; immunoregulation; improved; neonatal human; novel; novel therapeutic intervention; pathogen exposure; precursor cell; programs; receptor; receptor function; residence; response; therapeutic candidate; thymocyte; transcription factor; transcriptome; tumor

Project Summary InnateT cells are a collection of T cells withimportant regulatory functions that have a crucial role in immunity towards tumors, bacteria, viruses, and in cell-mediated autoimmunity. Due large quantities of cytokines upon activation, immune response populations glycolipid cells T commitment to innate T cells act as bridges between the innate and adaptive systems a nd ontribute greatly In mice, this swiftness of reflects their acquisition f functionality during their development in the thymus. Three major within the innate T cell group are recognized namely, the invariant NKT cells that recognize antigens presented by non-polymorphic CD1d molecules, the mucosal associated invariant T (MAIT) that recognize vitamin metabolites presented by the non-polymorphic MR1 molecules, and the certain  cells which antigen specificities remain uncertain. We have established an in vitro system t hat mimics the of double positive precursor cells to the innate T cell lineage and we propose to their ability to promptly secrete c to immune regulation and host protection. o , deconstruct the early transcriptional and epigenetic events that accompany this fate commitment (Aim 1). In this way, we will identify manipulation early factors that influence innate T cell development, providing the possibility for selective of innate T cell lineage specification. We will then investigatewhether human innate T cells acquire an innate-like transcriptional program in the thymus similarly to their mouse counterparts and whether this program is shared between the two species. To do so, we will profile the transcriptomes of iNKT and MAIT cells purified from neonatal human thymi at the single cell level. In addition, we will extend our knowledge of innate T cell lineage commitment by also studying CD1a-restricted T cells, which do not exist in mice (Aim 2). 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.

项目概要 先天T细胞是具有重要调节功能的T细胞的集合，在免疫中发挥着至关重要的作用 针对肿瘤、细菌、病毒和细胞介导的自身免疫。到期的 激活后产生大量细胞因子， 免疫 回复 人口 糖脂 细胞 时间 承诺 到 先天性 T 细胞充当先天性 T 细胞和适应性 T 细胞之间的桥梁 系统并在小鼠中做出了巨大贡献，这种速度 反映了它们在胸腺发育过程中获得的功能。三大 先天性 T 细胞群内被识别，即识别的不变 NKT 细胞 由非多态性 CD1d 分子呈递的抗原，即粘膜相关不变 T (MAIT) 识别由非多态性 MR1 分子呈现的维生素代谢物，以及某些  细胞的抗原特异性仍不确定。我们建立了一个模拟体外系统 双阳性前体细胞转化为先天 T 细胞谱系，我们建议 他们迅速分泌的能力 c 免疫调节和宿主保护。 哦 , 解构 伴随这种命运承诺的早期转录和表观遗传事件（目标 1）。这样，我们将 确认 操纵 影响先天性 T 细胞发育的早期因素，为选择性 先天 T 细胞谱系规范。然后我们将研究人类先天 T 细胞是否 在胸腺中获得类似于小鼠的先天转录程序，以及是否 该程序由两个物种共享。为此，我们将分析 iNKT 和 MAIT 的转录组 在单细胞水平上从新生儿人胸腺中纯化的细胞。此外，我们还将扩展我们的知识 通过研究小鼠中不存在的 CD1a 限制性 T 细胞来确定先天 T 细胞谱系的定型（目标 2）。 鉴于它们连接先天免疫和适应性免疫的关键炎症轴的能力，更好地理解 支持先天 T 细胞发育和可塑性的分子基础，以及这一特征的作用 由于它们的病理生理作用，对于开发新的治疗方法至关重要。