Transcriptional Regulation of Innate T cell fate

项目摘要 天然T细胞是T细胞的集合，具有重要的调节功能，在免疫中起着至关重要的作用 肿瘤、细菌、病毒和细胞介导的自身免疫。到期 激活后产生大量的细胞因子， 免疫 响应 人口 糖脂 单元格 T 承诺 至 先天T细胞是先天和后天之间的桥梁 在小鼠身上的系统和贡献很大，这种快速的 反映了他们在胸腺发育过程中获得的功能。三大 在先天T细胞组中被识别的是不变的NKT细胞 由非多态CD1d分子呈递的抗原，粘膜相关不变T(MAIT) 识别由非多态mr1分子提供的维生素代谢物，以及特定的 哪些细胞的抗原特异性仍不确定。我们已经建立了一个体外系统，它模仿了 先天T细胞谱系的双重阳性前体细胞，我们建议 它们迅速分泌的能力 C免疫调节和寄主保护。 O ， 解构 伴随这一命运承诺的早期转录和表观遗传事件(目标1)。通过这种方式，我们将 识别 手法 影响先天T细胞发育的早期因素，为选择性地 与生俱来的T细胞谱系特征。然后我们将研究人类先天T细胞 在胸腺中获得一个类似于小鼠的先天转录程序，以及 这个程序是在这两个物种之间共享的。为此，我们将介绍iNKT和MAIT的转录 从单细胞水平纯化的新生儿胸腺细胞。此外，我们还将扩大我们对 先天T细胞谱系承诺也研究CD1a限制的T细胞，这在小鼠中不存在(目标2)。 鉴于它们有能力将先天免疫和获得性免疫的关键炎症轴联系起来，更好地理解 支持先天性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 对于它们的病理生理作用，对于开发新的治疗方法是至关重要的。

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.