Regulation of T cell homeostasis and memory

T 细胞稳态和记忆的调节

基本信息

批准号：
8136584
负责人：
Linda Mac Pherson Bradley
金额：
$ 63.07万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8136584
关键词：
Acute Adhesions Adhesives Affect Apoptosis B-Lymphocytes Behavior Binding CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cell Adhesion Molecules Cell Death Cell Surface Proteins Cell physiology Cells Cessation of life Chimeric Proteins Chronic Clinical Collaborations Data Development Effector Cell Engineering Epidemic Event Family Funding Generations Genetic Goals Grant Hematopoietic Homeostasis Immune system Immunity In Vitro Individual Infection Influenza Instruction Interferon Type II Interferons Interleukin-17 L-Selectin Ligands Ligation Link Lung Lymphoid Maintenance Mediating Memory Modeling Mus P-selectin ligand protein Pathway interactions Phenotype Play Population Predisposition Property Proteins Regulation Reporter Role Selectins Signal Transduction T cell regulation T cell response T memory cell T-Lymphocyte T-Lymphocyte Subsets Time Transferase Transgenic Organisms Tuberculosis Vascular Endothelium Virus Virus Diseases carbohydrate binding protein cell motility cell type cytokine cytotoxic glycosylation in vivo influenzavirus insight lymph nodes migration novel pandemic influenza receptor binding response trait

项目摘要

Understanding mechanisms that regulate memory in T cells is crucial for developing strategies to protect against epidemic and pandemic influenza viruses. The goal of this project is to determine the contribution of the selectin family of adhesion molecules (E, P, and L) and the selectin ligand, PSGL-1, to T cell memory Recently, we found that glycosylated, biologically active ligands for selectins are acquired by a subset of CD4 and CD8 effectors in the draining lymph nodes after influenza virus infection and represent the majority of responding T cells in the lungs including IFN-g or IL-17 producers, in vivo correlates of Th1 and Th17 cells, respectively. Moreover, we find that a consistent fraction of memory phenotype T cells express selectin-binding activity, suggesting that this is a stable heritable trait that distinguishes a subset of memory cells. In the absence of functional selectin ligands or PSGL-1, CD4 cell expansion and localization in the lungs after influenza virus infection is unaltered. However, CD4 effectors produce elevated levels of IFN-g and IL-17 suggesting a role for selectin ligands in dampening the effector response. Importantly, the development of memory CD4 cells with the capacity for secondary expansion after infection is impaired, possibly because of altered homeostatic regulation. Our data support the hypothesis that mechanisms regulated by selectins can be essential for the delivery of signals that control CD4 effector cell responses as well as the homeostatic maintenance of a subset of memory cells. We will investigate the novel function(s) of selectins in the regulation of effector and memory T cells in following specific Aims: 1) to determine if differences in selectin-binding capacity identify memory T cell subsets with distinct functional properties and homeostatic regulation; 2) to investigate selectin-dependent responses of T cells and the role of selectin- binding capacity in the generation of memory cells after influenza virus infection; and 3) to identify mechanisms by which selectins regulate T cell homeostasis. We will take advantage of mice that are deficient in PSGL-1-/-, mice that lack PSGL-1 signaling, and mice that lack functional selectin ligands due to deficiency of the IV/VII fucosyl transferases. We will use IFN-g and IL-17 reporter mice, selectin ligand fusion proteins, and WT and engineered influenza viruses to enable us to assess the responses of polyclonal and TCR transgenic CD4 cells and make comparisons to CDS cells. In each of these Aims we will collaborate with Projects 1 and 2 to examine defined subsets of CD4 and CD8 cells in the influenza model. We will collaborate with project 4, which will determine the relevance of selectins in the tuberculosis model. RELEVANCE (See instructions): These studies together with those of projects 1, 2, and 4 will investigate means by which the immune system controls pulmonary infections and will provide new insights into the regulation of the development and homeostasis of memory T cells through mechanisms that regulate adhesion and migration that could be important for strategies to help protect the population from acute as well as chronic infections. Selectin- binding has the potential to be a new stable marker of memory T cells that have achieved effector function This would be an important breakthrough that could be extremely valuable in both clinical and basic studies.

了解调节 T 细胞记忆的机制对于制定保护策略至关重要对抗流行性和大流行性流感病毒。该项目的目标是确定以下人员的贡献粘附分子选择素家族（E、P 和 L）和选择素配体 PSGL-1 对 T 细胞记忆的影响最近，我们发现选择素的糖基化、生物活性配体是由一部分获得的流感病毒感染后引流淋巴结中的 CD4 和 CD8 效应细胞占大多数肺部应答 T 细胞（包括 IFN-g 或 IL-17 产生者）的数量，Th1 和 Th17 的体内相关性细胞，分别。此外，我们发现记忆表型 T 细胞的一致比例表达选择素结合活性，表明这是一种稳定的遗传性状，可以区分记忆的一个子集细胞。在缺乏功能性选择素配体或 PSGL-1 的情况下，CD4 细胞在流感病毒感染后，肺部没有变化。然而，CD4 效应子产生的 IFN-g 水平升高 IL-17 表明选择素配体在抑制效应反应中发挥作用。重要的是，感染后二次扩增能力受损的记忆 CD4 细胞的发育，可能是由于体内平衡调节的改变。我们的数据支持以下假设：机制受选择素调节对于控制 CD4 效应细胞反应的信号传递至关重要以及记忆细胞子集的稳态维持。我们将研究的新颖功能选择素在效应 T 细胞和记忆 T 细胞的调节中的作用如下： 1) 确定是否选择素结合能力的差异识别出具有不同功能特性的记忆T细胞亚群体内平衡调节； 2）研究T细胞的选择素依赖性反应以及选择素的作用流感病毒感染后记忆细胞生成的结合能力； 3) 识别选择素调节 T 细胞稳态的机制。我们将利用老鼠 PSGL-1-/- 缺陷的小鼠、缺乏 PSGL-1 信号传导的小鼠以及由于以下原因而缺乏功能性选择素配体的小鼠 IV/VII 岩藻糖基转移酶缺乏。我们将使用 IFN-g 和 IL-17 报告小鼠，选择素配体融合蛋白质、WT 和工程化流感病毒，使我们能够评估多克隆和 TCR 转基因 CD4 细胞并与 CDS 细胞进行比较。我们将在每一个目标中进行合作与项目 1 和 2 一起检查流感模型中定义的 CD4 和 CD8 细胞亚群。我们将与项目 4 合作，该项目将确定选择素在结核病模型中的相关性。相关性（参见说明）：这些研究与项目 1、2 和 4 的研究一起将研究免疫系统控制肺部感染，并将为疾病的发展和调节提供新的见解。通过调节粘附和迁移的机制来实现记忆 T 细胞的稳态对于帮助保护人们免受急性和慢性感染的战略非常重要。选择- 结合有可能成为已实现效应功能的记忆 T 细胞的新稳定标记这将是一个重要的突破，在临床和基础研究中都极具价值。