Development and function of innate-like gamma delta T cells

项目总结： 先天类γδT细胞是一种不寻常的T细胞，在肺、肠、肠等粘膜组织中高度浓缩， 以及皮肤，它们在宿主对病原体的免疫反应、自身免疫、抗病毒等方面发挥着关键作用。 肿瘤免疫，以及组织修复/动态平衡。与生俱来的γδT细胞的一个决定性特征是它们的能力 快速产生大量细胞因子(如干扰素-γ、白介素4和白介素17)、趋化因子和生长因子 这使得他们能够塑造正在形成的免疫反应的大小和质量。虽然 很大一部分γδT细胞表现出与生俱来的T细胞特征，这在小鼠和人类中都有证据 表明存在幼稚的、未极化的γδT细胞。这种机制/途径赋予了先天的 发育中的γδT细胞的表型在很大程度上仍未确定。我们最近公布的数据和初步数据 提示SLAM/SAP信号通路与先天性巨噬细胞的发育和功能密切相关。 就像γδT细胞一样，它通过多种不同的途径发挥作用。在这里，我们将使用单个单元格来处理S 多组学方法，包括SCCITESEQ与定制的γδV(D)J分析平台相结合，以及 SCATACseq定义区分SAP依赖的先天类γδT细胞的基因调控程序 发展。我们的初步数据表明，SLAM/SAP信号通路在非常早期就发挥了作用 参与了γδT细胞发育的研究，并揭示了γδ-T细胞的存在。 依赖的γδTCR克隆型。总而言之，这些已出版和未出版的文章让我们得出这样的假设 SLAM/SAP信号调节功能不同的先天γδTCRTCR克隆型的发育。为了测试 在这个假设中，我们将定义区分SAP依赖和SAP依赖的基因调控程序 发育过程中独立的胸腺γδT细胞和ii)定义SLAM/SAP 信号转导调节先天类γδT细胞的发育和功能。在完成这些目标后，我们预计 定义了新的依赖SAP的先天类γδT细胞亚群，并生成了一个全面的地图 不同发育阶段的γδT细胞依赖SAP的基因调控程序。此外, 我们将在定义一种调节先天类γδT的机制方面向前迈出重要的一步 细胞的发育和功能。我们相信，这一信息将是在定义 定义这些血统的发育要求以及它们对免疫的具体贡献 回应。

Project Summary: Innate-like γδ T cells are unusual T cells that are highly enriched in mucosal tissues like the lung, gut, and skin, where they play critical roles in the host immune response to pathogens, in autoimmunity, in anti- tumor immunity, and in tissue repair/homeostasis. A defining characteristic of innate-like γδ T cells is their ability to rapidly produce large amounts of cytokines (e.g., IFN-γ, IL-4, and IL-17), chemokines, and growth factors which allows them to shape both the magnitude and quality of both the developing immune response. Although a large fraction of γδ T cells exhibit innate-like T cell characteristics, evidence in both mouse and humans indicates the presence of naïve, unpolarized γδ T cells. The mechanisms/pathways that confer an innate-like phenotype on developing γδ T cells remain largely undefined. Both our recently published and preliminary data indicate that the SLAM/SAP signaling pathway is intimately involved in the development and function of innate- like γδT cells, and that it works through multiple distinct pathways. Here, w e p r o p o s e t o use a single-cell multiomics approach that includes scCITEseq coupled with a customized γδ V(D)J profiling platform and scATACseq to define the gene regulatory programs that distinguish SAP-dependent innate-like γδ T cells during development. Our preliminary data suggest that the SLAM/SAP signaling pathway functions at a very early stage of γδ T cell development, is involved in shaping the γδ TCR repertoire, and reveals the presence of SAP- dependent γδ TCR clonotypes. Altogether, these published and unpublished lead us to hypothesize that SLAM/SAP signaling regulates the development of functionally distinct innate-like γδ TCR clonotypes. To test this hypothesis, we will i) define the gene regulatory programs that distinguish SAP-dependent and SAP- independent thymic γδ T cells during development and ii) define the mechanisms through which SLAM/SAP signaling regulates innate-like γδ T cell developmental and function. Upon completion of these Aims, we expect to have defined new SAP-dependent innate-like γδ T cell subsets and to have generated a comprehensive map of the SAP-dependent gene regulatory programs of γδ T cells at different stages of development. In addition, we will have made a significant step forward in defining one of the mechanisms that regulates innate-like γδ T cell development and function. We believe this information will be a critical step forward in defining the developmental requirements that define these lineages as well as their specific contributions to the immune response.