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Expression and function of the TLRs on T cells

T 细胞上 TLR 的表达和功能

基本信息

批准号：
7544542
负责人：
Laurence A Turka
金额：
$ 37.44万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-01-01 至 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7544542
关键词：
Adaptor Signaling Protein Adoptive Transfer Alloantigen Backcrossings Binding Bone Marrow CD4 Positive T Lymphocytes Cell Survival Cells Chimera organism Complex Coupled Cytokine Signaling DNA Data Goals Immune Immune response Immune system Immunity Immunologic Monitoring In Vitro Individual Inflammatory Interleukin-12 Interleukin-2 Knockout Mice Laboratories Ligands Ligation MAP Kinase Gene MAPK14 gene MAPK8 gene MHC Class II Genes Mammals Mediating Mediator of activation protein Memory Microbe Modeling Molecular Mus Mutate NF-kappa B Pathway interactions Pattern Pattern recognition receptor Phagocytosis Play Production Proteins Reagent Receptor Activation Receptor Signaling Reporting Research Rest Retroviral Vector Role Signal Pathway Signal Transduction Signaling Molecule Stimulus System T-Cell Activation T-Lymphocyte TLR3 gene TLR9 gene TNFRSF5 gene Tissues Toll-Like Receptor 5 Toll-like receptors Toxoplasma gondii Transgenes Transgenic Mice Transgenic Organisms Transplantation Up-Regulation Work base cytokine eosinophil in vivo in vivo Model macrophage mast cell neutrophil pathogen programs receptor binding receptor expression receptor function reconstitution response

项目摘要

Toll-like receptors (TLRs) play an integral role in innate and adaptive immunity. Ligation of TLRs activates cells of the innate immune system, inducing functions such as phagocytosis and IFN-a and IFN-b secretion. TLR-ligation also serves as a bridge between the innate and adaptive immune systems. TLR stimulation of DCs and macrophages induces the production of inflammatory cytokines such as IL-12, and upregulation of MHC class II and costimulatory ligands such as CD40 and CD86, and most of these responses require signals delivered through the adaptor signaling molecule MyD88. While roles for TLRs and MyD88 on APCs are well-established, surprisingly little is known about their expression and potential function on T cells. Studies from our laboratory show that several TLRs are expressed following activation of naive CD4+CD25- T cells. Ligation of these TLRs activates, via MyD88, several downstream signaling pathways, including NF- kB, p38 JNK, and ERK. Functionally, this leads to enhanced T cell survival and provides costimulation with sub-optimal TCR ligation. New data also indicates that in vivo expression of MyD88 in T cells may be required for a protective immune response to the pathogen Toxoplasma gondii. Our working hypothesis is that TLR and MyD88 signaling on T cells are important contributors to cellular immune responses. To this end, the long-term goals of this research program are to define the expression and function of TLRs on T cells. In specific aim #1 we will characterize the signals which govern the expression and upregulation of TLRs on T cells, and the downstream signaling pathways which TLRs and MyD88 use to mediate their effects. Specific aim #2 will use cells from TCR transgenic mice coupled with in vitro and in vivo adoptive transfer systems to conduct a detailed examination of the effects of TLR and MyD88 activation of T cells on induction of activation and costimulatory molecules, cytokine production or skewing, and effector/memory differentiation and responsiveness. This approach will allow for precise definition of what TLR stimulation of T cells can do. In specific aim #3 we will then ask which of the functions identified for TLRs and MyD88 in aim #2 are operative during in vivo immune responses. To do so, we will use MyD88 knockout mice and bone-marrow chimeras and adoptive transfer systems to create in vivo models in which only T cells are deficient in MyD88. Based on our preliminary data, we will use these models to assess responses to Toxoplasma gondii, and will also backcross the MyD88-deficient mice onto TCR transgenic backgrounds to enable us to track the fate of individual T cells as they respond to alloantigen in vivo in transplantation models.

Toll 样受体 (TLR) 在先天免疫和适应性免疫中发挥着不可或缺的作用。 TLR 连接激活先天免疫系统的细胞，诱导吞噬作用以及 IFN-a 和 IFN-b 分泌等功能。 TLR 连接还充当先天性免疫系统和适应性免疫系统之间的桥梁。 TLR 刺激 DC 和巨噬细胞诱导炎症细胞因子（如 IL-12）的产生，并上调 MHC II 类和共刺激配体，例如 CD40 和 CD86，大多数这些反应都需要信号通过适配器信号分子 MyD88 传递。 TLR 和 MyD88 在 APC 上的角色虽然它们已经很成熟，但令人惊讶的是，人们对它们在 T 细胞上的表达和潜在功能知之甚少。我们实验室的研究表明，一些 TLR 在初始 CD4+CD25- 激活后表达。 T细胞。这些 TLR 的连接通过 MyD88 激活多个下游信号通路，包括 NF- kB、p38 JNK 和 ERK。从功能上讲，这会增强 T 细胞的存活率，并提供与 TCR 连接效果不佳。新数据还表明，T 细胞中 MyD88 的体内表达可能是对病原体弓形虫产生保护性免疫反应所需的。我们的工作假设是 T 细胞上的 TLR 和 MyD88 信号传导是细胞免疫反应。为此，本研究计划的长期目标是定义表达式以及 TLRs 对 T 细胞的功能。在具体目标#1中，我们将描述控制信号的特征 T细胞上TLRs的表达和上调，以及TLRs和TLRs的下游信号通路 MyD88用来调解它们的效果。具体目标#2 将使用来自 TCR 转基因小鼠的细胞，并结合体外和体内过继转移系统对 TLR 和 MyD88 激活 T 细胞，诱导激活和共刺激分子、细胞因子产生或偏差、效应器/记忆分化和响应能力。这种方法将允许精确 TLR 刺激 T 细胞可以做什么的定义。在具体目标#3中，我们将询问哪些功能目标 #2 中鉴定的 TLR 和 MyD88 在体内免疫反应期间发挥作用。为此，我们将使用MyD88敲除小鼠和骨髓嵌合体以及过继转移系统在体内创建仅 T 细胞缺乏 MyD88 的模型。根据我们的初步数据，我们将使用这些模型来评估对弓形虫的反应，并且还将 MyD88 缺陷小鼠回交到 TCR 转基因背景使我们能够追踪单个 T 细胞在响应时的命运移植模型中的体内同种异体抗原。