Development and function of innate-like gamma delta T cells

先天性γδT细胞的发育和功能

基本信息

批准号：
10527432
负责人：
JONATHAN E BOYSON
金额：
$ 23.4万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-18 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10527432
关键词：
Adaptor Signaling Protein Autoimmunity Biology Cell physiology Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Characteristics Coupled Custom Data Dependence Development Disease Exhibits Family Fetal Thymic Organ Culture Genetic Transcription Goals Growth Factor Health Hematopoietic Homeostasis Human Immune response Impairment Interferon Type II Interleukin-17 Interleukin-4 Lead 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

项目摘要

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/稳态是先天性 γδ T 细胞的一个决定性特征。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。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，赋予先天性类似的机制/途径。我们最近发表的数据和初步数据仍然很大程度上未定义。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。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 定义基因调控程序，区分 SAP 依赖性先天样 γδ T 细胞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-的存在总而言之，这些已发表和未发表的 γδ TCR 克隆型促使我们追寻这一点。 SLAM/SAP 信号传导调节功能独特的先天样 γδ TCR 克隆型的发育。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 的机制我们期望完成这些目标后，信号传导可调节先天性 γδ T 细胞的发育和功能。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此外，γδ T 细胞在不同发育阶段的 SAP 依赖性基因调控程序。我们将在定义调节先天性 γδ T 的机制方面迈出重要一步我们相信这些信息将是定义细胞发育和功能的关键一步。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。