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: 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
• 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

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.

项目摘要： 先天性的γδT细胞是异常的T细胞，高度富集在肺，肠道等粘膜组织中 和皮肤，它们在宿主对病原体的免疫反应中起关键作用，自身免疫，抗 肿瘤免疫，在组织修复/稳态中。先天性γδT细胞的定义特征是它们的能力 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 这使他们能够塑造发展免疫反应的大小和质量。虽然 一大量的γδT细胞表现出先天的T细胞特征，在小鼠和人类中都证明 表明存在幼稚的，未熟化的γδT细胞。会议的机制/途径会导致先天性 开发γδT细胞的表型在很大程度上仍然不确定。我们最近发布的数据和初步数据 表明SLAM/SAP信号通路与先天性的发展和功能密切相关 像γδT细胞一样，它通过多个不同的途径工作。在这里，使用单细胞 包括scciteseq的多组学方法以及定制的γδV（d）J分析平台和 scatacseq定义基因调节程序，以区分SAP依赖性的先天样γδT细胞 发展。我们的初步数据表明，SLAM/SAP信号通路在很早的阶段起作用 γδT细胞发育的涉及γδTCR库，并揭示了SAP-的存在 依赖性γδTCR锁骨型。这些出版和未发表的总共使我们假设 SLAM/SAP信号传导调节功能不同的先天样γδTCR锁骨的发展。测试 这个假设，我们将定义区分SAP依赖性和SAP-的基因调节程序 在开发过程中和ii）定义了猛击/SAP的机制，独立的胸腺γδT细胞 信号传导调节先天样γδT细胞的发育和功能。这些目标完成后，我们期望 为了定义新的依赖SAP的先天样γδT细胞子集，并产生了一个全面的图 在不同发育阶段，γδT细胞的SAP依赖性基因调节程序。此外， 我们将在定义调节先天样γδT的一种机制方面迈出了重要的一步 细胞发育和功能。我们认为，这些信息将是定义的关键一步 定义这些谱系及其对免疫的特定贡献的发展要求 回复。