Development and function of innate-like gamma delta T cells

项目概要： 先天性γδ T细胞是一种不寻常的T细胞，在肺、肠、 和皮肤，它们在宿主对病原体的免疫应答、自身免疫、抗- 肿瘤免疫和组织修复/体内平衡。先天性γδ T细胞的一个定义特征是它们能够 为了快速产生大量的细胞因子（例如，IFN-γ、IL-4和IL-17）、趋化因子和生长因子 这使得他们能够塑造发展中的免疫反应的大小和质量。虽然 大部分γδ T细胞表现出先天性T细胞样特征，在小鼠和人类中均有证据表明， 表明存在幼稚的未极化γδ T细胞。赋予先天性类 在发育中的γδ T细胞上的表型在很大程度上仍然不确定。我们最近公布的数据和初步数据 表明SLAM/SAP信号通路密切参与先天性巨噬细胞的发育和功能， 就像γδT细胞一样，它通过多种不同的途径发挥作用。在这里，我们使用单细胞 多组学方法，包括scCITEseq与定制的γδ V（D）J分析平台相结合， scATACseq来定义区分SAP依赖性先天样γδ T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的阶段起作用 γδ T细胞的发育，参与形成γδ TCR库，并揭示了SAP的存在。 依赖性γδ TCR克隆型。总而言之，这些已发表和未发表的文章让我们假设， SLAM/SAP信号传导调节功能不同的先天性γδ TCR样克隆型的发育。测试 根据这一假设，我们将i）定义区分SAP依赖性和SAP- ii）定义SLAM/SAP通过其表达的机制， 信号转导调节天然样γδ T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SAP依赖性先天样γδ T细胞亚群，并生成了一个全面的图谱， SAP依赖的γδ T细胞在不同发育阶段的基因调控程序。此外，本发明还提供了一种方法， 我们将在确定调节先天性γδ T的机制方面迈出重要的一步 细胞发育和功能。我们认为，这一信息将是向前迈出的关键一步， 定义这些谱系的发育要求以及它们对免疫系统的特定贡献 反应

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 Altogether, these published and unpublished lead us to hypothesize that SLAM/SAP signaling regulates the development of functionally distinct innate-like γδ TCR clonotypes.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.