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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：
7337092
负责人：
Laurence A Turka
金额：
$ 39.28万
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/7337092
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样受体在先天免疫和获得性免疫中起着不可或缺的作用。TLRs的结扎激活先天免疫系统的细胞，诱导吞噬和分泌干扰素-a和干扰素-b等功能。 TLR连接也是先天免疫系统和获得性免疫系统之间的桥梁。TLR刺激 DC和巨噬细胞诱导炎性细胞因子的产生，如IL-12，并上调 MHC II类和共刺激配体，如CD40和CD86，这些反应中的大多数需要通过接头信号分子MyD88传递的信号。而TLR和MyD88在APC上的角色都是成熟的，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，在幼稚的CD4+CD25激活后，有几个TLR表达- T细胞。这些TLR的连接通过MyD88激活了几个下游信号通路，包括NF-1。 Kb、p38、JNK和ERK。在功能上，这会增强T细胞的存活率，并提供与次优的TCR结扎。新数据还表明，MyD88在T细胞中的体内表达可能是对弓形虫病原体的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信号是细胞内免疫反应。为此，这项研究计划的长期目标是定义以及TLRs在T细胞上的功能。在具体目标#1中，我们将描述支配 T细胞上TLRs的表达和上调，以及TLRs和TLRs的下游信号通路 MyD88用来调节它们的影响。特殊目标2将使用来自TCR转基因小鼠的细胞与In 体外和体内采用转移系统，以进行详细的检查TLR和 MyD88对T细胞活化及共刺激分子、细胞因子产生的诱导作用偏斜，以及效应器/记忆的分化和反应。这种方法将允许精确地定义TLR对T细胞的刺激作用。在具体目标#3中，我们将询问以下哪些功能在AIM#2中发现的TLRs和MyD88在体内免疫反应期间起作用。要做到这一点，我们将利用MyD88基因敲除小鼠和骨髓嵌合体和过继转移系统在体内建立只有T细胞缺乏MyD88的模型。根据我们的初步数据，我们将使用这些评估弓形虫反应的模型，并将MyD88缺陷小鼠回交到 TCR转基因背景使我们能够跟踪单个T细胞在它们对移植模型中的体内同种异体抗原。