Functional dissection of the Klrg1+ regulatory T cell subset in health and diseases

Klrg1 调节性 T 细胞亚群在健康和疾病中的功能剖析

• 批准号: 10427428
• 负责人: Li-Fan Lu
• 金额: $ 19.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10427428
• 关键词: Ablation; Affect; Animal Model; Antigens; Autoimmune; Autoimmune Diseases; Autoimmunity; Biological; Cells; Cellular biology; Colitis; Colon; Data; Development; Differentiation Antigens; Disease; Dissection; Employment; Enterobacteria phage P1 Cre recombinase; Exhibits; Foundations; Frequencies; Future; Gene Expression Profiling; Genes; Genetic Models; Goals; Health; Heterogeneity; Homeostasis; Human; Immune; Immune System Diseases; Immune Tolerance; Immune response; Immune system; Immunologics; Individual; Inflammation; Intestines; Knowledge; Lead; Literature; Mediating; Methods; Modeling; Molecular; Mus; Natural Killer Cells; Normal tissue morphology; PTPRC gene; Pathologic; Peripheral; Phenotype; Physiological; Population; Prevalence; Regulatory T-Lymphocyte; Reporting; Research; Role; Small Intestines; Solid; Spleen; T-Cell Depletion; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; base; differential expression; effector T cell; experience; immune activation; immunoregulation; in vivo; insight; interest; mouse model; novel; novel therapeutics; pathogenic microbe; peripheral tolerance; single cell sequencing; single-cell RNA sequencing; transcriptomics

In the past two decades, regulatory T (Treg) cells have emerged as a dedicated immune population crucial for the negative regulation of immune responses. Nonetheless, the precise effector mechanisms underlying Treg cell-mediated suppression in a specific tissue microenvironment under a particular immunological condition remains incompletely understood. To date, accumulating evidence has suggested that similar to the conventional T (Tconv) cells they regulate, Treg cells come in “different flavors” both phenotypically and functionally. In addition to the heterogeneity of the Treg cells that control different types of T cell immune responses, the presence of distinct Treg cell populations in many nonlymphoid tissues have also started to be appreciated. In this proposal, though establishing a novel mouse model that could allow us to deplete a desired Treg cell subset in a temporally controlled manner, we will determine the cellular role of a specific Klrg1-expressing Treg cell population in maintaining peripheral tissue homeostasis under both physiologic and pathologic conditions. Moreover, by employing a cutting-edge single-cell transcriptomic approach, we will gain further molecular and cellular insights into the impact of Klrg1+ Treg cell depletion on the immune system in a particular tissue microenvironment in an unbiased manner. Collectively, our proposed studies will not only provide a comprehensive assessment of the Klrg1+ Treg cell subset in Treg cell-mediated immune regulation but will also facilitate a better understanding of the potential effector mechanisms by which Klrg1+ Treg cells maintain peripheral tissue homeostasis. Accomplishing the aims proposed in this application will undoubtedly extend our fundamental knowledge of a distinct Treg cell subset in immune regulation and provide further insights into the development of new therapeutic means targeting Treg cells to treat a wide range of human immune disorders.

在过去的二十年里，调节性T(Treg)细胞已经成为一种专门的免疫群体，对 免疫反应的负性调节。尽管如此，Treg背后的精确效应器机制 特定免疫条件下特定组织微环境中细胞介导的抑制 仍然没有完全被理解。到目前为止，积累的证据表明，类似于 传统的T(Tconv)细胞受其调节，Treg细胞具有不同的表型和 在功能上。除了控制不同类型T细胞免疫的Treg细胞的异质性 在许多非淋巴组织中，不同的Treg细胞群的存在也开始 感激不尽。在这项提议中，尽管建立一种新的老鼠模型可以让我们消耗一种 所需的Treg细胞亚群以时间受控的方式，我们将确定特定的细胞角色 两种生理状态下表达Klrg1的Treg细胞群在维持外周组织内稳中的作用 以及病态的情况。此外，通过采用尖端的单细胞转录切割方法，我们 将获得进一步的分子和细胞洞察Klrg1+Treg细胞枯竭对免疫的影响 系统在特定的组织微环境中以无偏见的方式。总的来说，我们建议的研究将 不仅提供了对Treg细胞介导的免疫中Klrg1+Treg细胞亚群的全面评估 调节，也将有助于更好地理解Klrg1+ Treg细胞维持外周组织的动态平衡。实现本申请中提出的目标将 毫无疑问，我们对免疫调节和免疫调节中的一个独特的Treg细胞亚群的基础知识得到了扩展 为开发以Treg细胞为靶点的新治疗手段提供进一步的见解 一系列人类免疫紊乱。