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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：
7162068
负责人：
Laurence A Turka
金额：
$ 40.17万
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 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7162068
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

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：Toll样受体（TLR）在先天性和适应性免疫中起着不可或缺的作用。TLR的连接激活先天性免疫系统的细胞，诱导诸如吞噬作用和IFN-α和IFN-b分泌的功能。TLR-连接还充当先天性和适应性免疫系统之间的桥梁。DC和巨噬细胞的TLR刺激诱导炎性细胞因子如IL-12的产生，以及MHC II类和共刺激配体如CD40和CD86的上调，并且大多数这些应答需要通过接头信号传导分子MyD88递送的信号。虽然TLR和MyD88在APC上的作用已经很好地建立，但令人惊讶的是，关于它们在T细胞上的表达和潜在功能知之甚少。来自我们实验室的研究表明，在初始CD4 + CD25 T细胞活化后表达几种TLR。这些TLR的连接通过MyD88激活几种下游信号通路，包括NF-κ B、p38 JNK和ERK.在功能上，这导致增强的T细胞存活并提供与次优TCR连接的共刺激。新的数据还表明，MyD88在T细胞中的体内表达可能是对病原体弓形虫的保护性免疫应答所必需的。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应答的重要贡献者。为此，本研究计划的长期目标是确定T细胞上TLR的表达和功能。在具体目标#1中，我们将表征控制T细胞上TLR表达和上调的信号，以及TLR和MyD88用于介导其作用的下游信号传导途径。具体目标#2将使用来自TCR转基因小鼠的细胞与体外和体内过继转移系统偶联，以详细检查T细胞的TLR和MyD88活化对活化和共刺激分子的诱导、细胞因子产生或偏斜以及效应子/记忆分化和响应性的影响。这种方法将允许精确定义TLR刺激T细胞可以做什么。在具体目标#3中，我们将询问目标#2中针对TLR和MyD88鉴定的哪些功能在体内免疫应答期间起作用。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来创建体内模型，其中只有T细胞缺乏MyD88。基于我们的初步数据，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转基因背景上，以使我们能够在移植模型中追踪个体T细胞在体内对同种异体抗原反应时的命运。