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.

项目摘要 先天性T细胞是具有重要调节功能的T细胞的集合，在免疫中具有至关重要的作用 针对肿瘤、细菌、病毒和细胞介导的自身免疫。由于 激活后产生大量细胞因子， 免疫 响应 人口 糖脂 细胞 不 承诺 到 先天性T细胞是先天性和适应性T细胞之间的桥梁。 在小鼠中， 反映了它们在胸腺发育期间获得的功能。三大 在先天性T细胞群内的NKT细胞被识别，即识别 由非多态性CD1d分子、粘膜相关不变T（MAIT）呈递的抗原 识别由非多态性MR1分子呈现的维生素代谢物， 抗原特异性仍然不确定的细胞。我们已经建立了一个体外系统， 双阳性前体细胞的先天性T细胞谱系，我们建议， 它们迅速分泌 c.免疫调节和宿主保护。 O , 解构 早期转录和表观遗传事件伴随着这种命运的承诺（目标1）。以此来 识别 操纵 影响先天性T细胞发育的早期因素，为选择性免疫提供了可能性。 先天性T细胞谱系的特化。然后我们将研究人类先天性T细胞 在胸腺中获得类似于小鼠的先天转录程序， 这个程序是两个物种共享的。为此，我们将分析iNKT和MAIT的转录组， 在单细胞水平从新生人胸腺纯化的细胞。此外，我们将扩大我们的知识， 先天性T细胞谱系定型也通过研究小鼠中不存在的CD1a限制性T细胞（Aim 2）。 鉴于它们能够连接先天性和适应性免疫的关键炎症轴， 支持先天T细胞发育和可塑性的分子基础，以及这一特征在多大程度上解释了 对于开发新的治疗方法至关重要。