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病媒传播疾病，由螺旋体（伯氏疏螺旋体）通过蜱虫肩胛硬蜱传播引起。莱姆病的临床表现之一是关节炎，它可以成为慢性和耐抗生素。一个显着比例的淋巴细胞积累在莱姆关节炎滑液是γ/δ（？Vd 1亚群的T细胞。我们已经确定滑膜V41细胞对B有高度反应。伯氏菌脂肽（结合Toll样受体2，TLR 2）表达高水平的Fas-Ligand（FasL），可能与CD 1b反应，并且类似于慢性激活的T细胞。此外，Vd 1细胞通过FasL刺激树突状细胞（DC）的效应子功能，其然后反馈以激活Vd 1细胞。由于Fas死亡受体抑制剂c-FLIP的高水平表达，DC对FasL介导的细胞死亡具有抗性。c-FLIP将信号从caspase级联转移到NF-？B途径。因此，Fas/FasL可能是一个重要的联系？T细胞和DC的活化。缺乏功能性FasL的小鼠表现出用B减轻的炎症和关节炎。伯氏感染因此，该项目研究了莱姆关节炎的三个密切相关的组成部分：B。Burgdorferi、滑膜Vd 1 T细胞和树突状细胞（DC）。连接这三个部分的模型是B。burgdorferi结合DC上的TLR，其信号传导分子如CD 1b的上调，所述分子刺激滑膜Vd 1细胞。这也将通过用B体内感染来研究。在缺乏TLR、MyD 88或CD 1d的小鼠中，还将制备可溶性VdlTCR以鉴定其它Vdl配体（Aim 1）。滑膜Vd 1细胞被CD 1b和疏螺旋体脂肽以及其TCR/CD 3组成的固有特性反复激活，导致表面Fas配体（FasL）的高水平表达（Aim 2）。DC反过来也通过FasL从V41细胞接收刺激信号。在DC中存在高水平的Fas抑制剂FLIP时，Fas信号通过NF-κ B从死亡途径转向生长和分化信号。B。这通过衔接蛋白RIP 1和TRAF 2向c-FLIP的募集而发生。DC的TLR信号传导也可能需要caspase-8并通过TRAF 6连接。最后，Fas/FasL的体内作用将通过FasL+？？在巨噬细胞和/或DC中选择性地将T细胞移植到携带突变型FasL或缺乏Fas、半胱天冬酶-8或c-FLIP的小鼠（Aim 3）。这项工作代表了唯一已知的人类研究？？莱姆关节炎中的T细胞Project Narrative？？T细胞仍然是免疫系统中的一个谜。它们通常位于上皮屏障，并被认为参与对各种感染的最初反应。实际上是一种保护作用？？在各种感染模型中观察到T细胞。??在自身免疫综合征中，T细胞也在炎症部位聚集，例如在类风湿性关节炎中的滑膜组织中，在乳糜泻中的肠中，或在结节病中的肺中。然而，几乎没有什么是关于特异性的？？T细胞。因此，我们使用人类和小鼠的莱姆关节炎作为模型？T细胞在感染和潜在的自身免疫情况下的反应，因为患有慢性抗风湿性莱姆病关节炎的患者在滑膜组织的组成、对免疫抑制剂的反应以及甚至相同的HLA-DR 4关联方面与自身免疫性类风湿性关节炎非常相似。该项目将寻求使用可溶性TCR-Vd 1建立滑膜Vd 1细胞的特异性，以及通过Fas-配体的高表达及其通过Fas刺激树突状细胞的能力来建立其效应器功能。了解这些相互作用将提高我们的理解如何？T细胞在感染和自身免疫性疾病期间调节免疫应答。