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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

基本信息

批准号：
10287917
负责人：
Li-Fan Lu
金额：
$ 23.7万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
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/10287917
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

项目摘要

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.

在过去的二十年中，调节性T（Treg）细胞已经成为一种专用的免疫群体，对免疫系统的免疫调节至关重要。免疫反应的负调节。尽管如此，Treg的精确效应机制在特定免疫条件下，在特定组织微环境中的细胞介导的抑制仍然不完全理解。迄今为止，越来越多的证据表明，类似于与它们调节的常规T（Tconv）细胞不同，Treg细胞在表型和功能上。除了控制不同类型T细胞免疫的Treg细胞的异质性外，在免疫应答中，许多非淋巴组织中不同Treg细胞群的存在也开始受到影响。赞赏.在这项提议中，虽然建立了一种新的小鼠模型，可以让我们消耗一种我们将以时间控制的方式确定所需Treg细胞亚群的细胞作用， Klrg1表达Treg细胞群在维持外周组织稳态中的作用和病理条件。此外，通过采用尖端的单细胞转录组学方法，我们将获得进一步的分子和细胞见解Klrg1+ Treg细胞耗竭对免疫系统的影响，系统在特定组织微环境中以无偏的方式。总的来说，我们提出的研究将不仅提供了Treg细胞介导的免疫反应中Klrg1+ Treg细胞亚群的全面评估，调节，但也将有助于更好地了解潜在的效应机制，Klrg1+ Treg细胞维持外周组织稳态。实现本申请中提出的目的将毫无疑问地扩展了我们对免疫调节中不同Treg细胞亚群的基本知识，为靶向Treg细胞的新治疗手段的发展提供了进一步的见解，以治疗广泛的一系列人类免疫系统疾病