Development and function of innate-like gamma delta T cells

先天性γδT细胞的发育和功能

• 批准号: 10624417
• 负责人: JONATHAN E BOYSON
• 金额: $ 19.5万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-18 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624417
• 关键词: Adaptor Signaling Protein; Autoimmunity; Biology; Cell physiology; Cells; Characteristics; Coupled; Data; Dependence; Development; Disease; Exhibits; Family; Fetal Thymic Organ Culture; Genetic Transcription; Goals; Growth Factor; Health; Hematopoietic; Homeostasis; Human; IL17 gene; Immune response; Impairment; Innate Immune Response; Interferon Type II; Interleukin-4; Leukocytes; Lung; Malignant Neoplasms; Maps; Mucous Membrane; Mus; Pathway interactions; Phenotype; Play; Publishing; Receptor Signaling; Regulator Genes; Reporter; Research Proposals; Role; SH2D1A gene; SLAM family receptor; Shapes; Signal Pathway; Signal Transduction; Skin; System; T-Cell Development; T-Lymphocyte; T-Lymphocyte Subsets; T-cell receptor repertoire; Testing; Thymus Gland; Tumor Immunity; Work; adaptive immune response; chemokine; cytokine; multiple omics; novel; pathogen; programs; proteogenomics; receptor; tissue repair; tool; γδ T cells

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.

项目概要： 先天性 γδ T 细胞是一种不寻常的 T 细胞，在肺、肠道等粘膜组织中高度富集。 和皮肤，它们在宿主对病原体的免疫反应、自身免疫、抗 肿瘤免疫和组织修复/稳态。先天性 γδ T 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（例如 IFN-γ、IL-4 和 IL-17）、趋化因子和生长因子 这使他们能够塑造正在发展的免疫反应的程度和质量。虽然 大部分 γδ T 细胞表现出先天性 T 细胞特征，小鼠和人类的证据 表明存在幼稚的、未极化的 γδ T 细胞。赋予先天性的机制/途径 γδ T 细胞发育的表型在很大程度上仍不明确。我们最近发布的数据和初步数据 表明 SLAM/SAP 信号通路与先天神经系统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，我们建议使用单细胞 多组学方法，包括 scCITEseq 与定制的 γδ V(D)J 分析平台相结合， scATACseq 定义了区分 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发挥作用 γδ T 细胞发育的重要组成部分，参与形成 γδ TCR 库，并揭示了 SAP-的存在 依赖的 γδ TCR 克隆型。总而言之，这些已发表和未发表的内容使我们推测 SLAM/SAP 信号传导调节功能独特的先天样 γδ TCR 克隆型的发育。测试 根据这个假设，我们将 i) 定义区分 SAP 依赖性和 SAP- 的基因调控程序 ii) 定义 SLAM/SAP 的机制 信号传导调节先天性 γδ T 细胞的发育和功能。完成这些目标后，我们期望 定义了新的 SAP 依赖性先天性 γδ T 细胞亚群并生成了综合图谱 γδ T 细胞在不同发育阶段的 SAP 依赖性基因调控程序。此外， 我们将在定义调节先天性 γδ T 的机制方面迈出重要一步 细胞发育和功能。我们相信这些信息将成为定义 定义这些谱系的发育要求以及它们对免疫的具体贡献 回复。