Gamma Delta T Cells in Lyme Arthritis

莱姆关节炎中的 Gamma Delta T 细胞

• 批准号: 7932685
• 负责人: Ralph C Budd
• 金额: $ 24.08万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-23 至 2013-09-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7932685
• 关键词: Adaptor Signaling Protein; Address; Adoptive Transfer; Affinity; Antibiotic Resistance; Antigens; Arthritis; Autoimmune Process; Avidin; Back; Baculoviruses; Binding; Black-legged Tick; Bone Marrow; Borrelia; Borrelia Infections; Borrelia burgdorferi; CASP8 and FADD-like apoptosis regulating protein; CD1b antigen; Caspase; Celiac Disease; Cell Death; Cells; Cessation of life; Chronic; Clinical; Complement component C1r; Complex; Coupled; Dendritic Cells; Differentiation and Growth; Epithelial; Figs - dietary; HLA-DR4 Antigen; Heart; Human; Immune response; Immune system; Immunosuppressive Agents; In Vitro; Infection; Infiltration; Inflammation; Inflammatory Response; Intestines; Knockout Mice; Ligands; Ligation; Link; Lung; Lyme Arthritis; Lyme Disease; Lymphocyte; Mediating; Modeling; Molecular; Monitor; Mus; Nickel; Order Spirochaetales; OspA protein; Pathway interactions; Patients; Production; Property; Proteins; Receptor Activation; Receptor Signaling; Recruitment Activity; Research; Resistance; Rheumatoid Arthritis; Role; Sarcoidosis; Signal Transduction; Site; Small Interfering RNA; Specificity; Surface; Syndrome; Synovial Fluid; T-Cell Activation; T-Lymphocyte; TRAF2 gene; TRAF6 gene; Testing; Ticks; Tissues; Toll-Like Receptor 2; Toll-like receptors; Tumor Necrosis Factor Ligand Superfamily Member 6; Up-Regulation; Work; antigen binding; caspase-8; cytokine; defined contribution; expression vector; feeding; improved; in vivo; inhibitor/antagonist; macrophage; monocyte; mutant; receptor; response; transmission process; vector

DESCRIPTION (provided by applicant): Lyme Disease is the most common vector-borne illness in the U.S. and is caused by transmission of the spirochete, Borrelia burgdorferi, via the tick Ixodes scapularis. Among the clinical manifestations of Lyme Disease is arthritis, which can become chronic and resistant to antibiotics. A significant proportion of the lymphocytes that accumulate in Lyme arthritis synovial fluid are gamma/delta (??? T cells of the Vd1 subset. We have determined that the synovial V41 cells are highly responsive to B. burgdorferi lipopeptides (that bind Toll-like Receptor 2, TLR2), express high levels of Fas-Ligand (FasL), may react to CD1b, and resemble chronically activated T cells. Furthermore, the Vd1 cells stimulate effector function of dendritic cells (DC) via FasL, which then feeds back to activate the Vd1 cells. DC are resistant to FasL-mediated cell death due to high level expression of the Fas death receptor inhibitor, c-FLIP. c-FLIP diverts signals from the caspase cascade and toward the NF-?B pathway. Thus, Fas/FasL may be an important link between ?? T cells and activation of DC. Mice lacking functional FasL manifest reduced inflammation and arthritis with B. burgdorferi infection. This project thus examines three closely related components of Lyme arthritis: B. burgdorferi, synovial Vd1 T cells, and dendritic cells (DC). The model connecting these three components is that B. burgdorferi binds TLR on DC, which signal upregulation of molecules such as CD1b that are stimulatory for synovial Vd1 cells. This will be also studied by in vivo infection with B. burgdorferi in mice lacking TLR, MyD88, or CD1d. A soluble Vd1 TCR will also be made to identify other Vd1 ligands (Aim 1). The synovial Vd1 cells become repeatedly activated by CD1b and Borrelia lipopeptides, as well as by properties intrinsic to their TCR/CD3 composition, which results in high level expression of surface Fas-ligand (FasL) (Aim 2). DC in turn receive stimulatory signals also via FasL from V41 cells. In the presence of high levels of the Fas inhibitor FLIP in DC, Fas signals are diverted from death pathways to growth and differentiation signals via NF-?B. This occurs via recruitment to c-FLIP of the adaptor proteins, RIP1 and TRAF2. TLR signaling of DC may also require caspase-8 and connect via TRAF6. Finally, the in vivo role of Fas/FasL will be studied by adoptive transfer of FasL+ ?? T cells to mice bearing mutant FasL or lacking Fas, caspase-8, or c-FLIP selectively in macrophages and/or DC (Aim 3). This work represents the only known research on human ?? T cells in Lyme arthritis. Project Narrative ?? T cells remain an enigma in the immune system. They are often localized at epithelial barriers, and are felt to be involved in the initial response to various infections. Indeed a protective role of ?? T cells has been observed in various infectious models. ?? T cells also accumulate at sites of inflammation in autoimmune syndromes such as in the synovial tissue in rheumatoid arthritis, the bowel in celiac disease, or the lungs in sarcoidosis. However, almost nothing is nothing regarding the specificity of ?? T cells. We are thus using Lyme arthritis in humans and mice as a model of the ?? T cell response in infection and potentially an autoimmune situation, as patients with chronic antibiotic-resistant Lyme arthritis closely resemble autoimmune rheumatoid arthritis in the composition of the synovial tissue, response to immunosuppressive agents, and even the same HLA-DR4 association. This project will seek to establish both the specificity of synovial Vd1 cells using a soluble TCR-Vd1, as well as their effector function through high expression of Fas- ligand and their ability to stimulate dendritic cells by Fas. Understanding these interactions will improve our understanding of how ?? T cell regulate the immune response during infection and autoimmune conditions.

描述（由申请人提供）：莱姆病是美国最常见的媒介传播疾病，是由螺旋体传播（通过tick ixodes scapularis）传播的。莱姆病的临床表现包括关节炎，可以变得长期对抗生素具有抗性。 A significant proportion of the lymphocytes that accumulate in Lyme arthritis synovial fluid are gamma/delta (??? T cells of the Vd1 subset. We have determined that the synovial V41 cells are highly responsive to B. burgdorferi lipopeptides (that bind Toll-like Receptor 2, TLR2), express high levels of Fas-Ligand (FasL), may react to CD1b, and慢性地激活了T细胞，VD1细胞通过FASL刺激树突状细胞的效应功能，然后将其返回以激活VD1细胞。 FAS/FASL可能是T细胞的重要联系和缺乏功能性FASL的小鼠。连接这三个组成部分的模型是B. burgdorferi在DC上结合TLR，该模型表明了对滑膜VD1细胞的刺激性分子（例如CD1B）的上调。在缺乏TLR，MyD88或CD1D的小鼠中，体内感染的体内感染也将通过体内感染进行研究。还将制定可溶性VD1 TCR来识别其他VD1配体（AIM 1）。滑膜VD1细胞被CD1b和脂肪肽以及其TCR/CD3组成固有的特性反复激活，从而导致表面FAS-ligand（FASL）的高水平表达（AIM 2）。 DC反过来也通过V41细胞的FASL接收刺激信号。在DC中FAS抑制剂的高水平存在的情况下，FAS信号通过NF- b从死亡途径转移到生长和分化信号。这是通过募集到适配器蛋白RIP1和TRAF2的C翼的募集而发生的。 DC的TLR信号传导也可能需要caspase-8并通过TRAF6连接。最后，FAS/FASL的体内作用将通过FASL+的过继转移来研究。在巨噬细胞和/或DC中选择性选择性地携带突变体FASL或缺乏FAS，CASPASE-8或C-FLIP的T细胞（AIM 3）。这项工作代表了关于人类的唯一已知研究？莱姆关节炎中的T细胞。项目叙述？ T细胞在免疫系统中仍然是一个谜。它们通常位于上皮障碍物，并被认为参与了对各种感染的最初反应。确实是保护性？在各种感染模型中已经观察到T细胞。 ？ T细胞还积聚在自身免疫性综合征的炎症部位，例如类风湿关节炎，肠胃病的肠或结节病中的肺部的滑肠。但是，关于特殊性几乎没有什么？ T细胞。因此，我们在人类和小鼠中使用莱姆关节炎作为？由于慢性抗生素关节炎的患者在滑膜组织的组成中，T细胞反应与慢性抗生素关节炎的患者在滑膜组织组成，对免疫抑制剂的反应中，甚至相同的HLA-DR4缔合的反应非常相似。该项目将寻求使用可溶性TCR-VD1来建立滑膜VD1细胞的特异性，及其通过高表达Fas含量的效应函数及其效应函数，以及它们通过FAS刺激树突状细胞的能力。了解这些互动将提高我们对如何的理解？ T细胞调节感染和自身免疫性条件期间的免疫反应。