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，由螺旋体，伯氏疏螺旋体，通过肩胛骨伊蚊传播引起。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。在莱姆病的滑液中积累的淋巴细胞中有很大一部分是γ / δ （???）Vd1子集的T细胞。我们已经确定滑膜V41细胞对伯氏疏杆菌脂肽（结合toll样受体2，TLR2）高度敏感，表达高水平的fas配体（FasL），可能对CD1b产生反应，类似于慢性活化的T细胞。此外，Vd1细胞通过FasL刺激树突状细胞（DC）的效应功能，然后FasL反馈激活Vd1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caspase级联的信号转移到NF-？B通路。因此，Fas/FasL可能是？？T细胞和DC的激活。缺乏功能性FasL的小鼠表现为伯氏疏螺旋体感染的炎症和关节炎减轻。因此，该项目研究了莱姆病的三个密切相关的组成部分：伯氏疏螺旋体、滑膜Vd1 T细胞和树突状细胞（DC）。连接这三种成分的模型是伯氏疏螺旋体将TLR结合在DC上，这表明刺激滑膜Vd1细胞的CD1b等分子上调。这也将通过在缺乏TLR、MyD88或CD1d的小鼠体内感染伯氏疏螺旋体来研究。可溶性Vd1 TCR也将用于鉴定其他Vd1配体（目的1）。滑膜Vd1细胞被CD1b和疏螺旋体脂肽以及其TCR/CD3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也通过FasL接收来自V41细胞的刺激信号。在DC中存在高水平的Fas抑制剂FLIP时，Fas信号通过NF- B从死亡途径转移到生长和分化信号。这是通过对接头蛋白RIP1和TRAF2的c-FLIP的招募而发生的。DC的TLR信号也可能需要caspase-8，并通过TRAF6连接。最后，通过FasL+ ??的过继转移来研究Fas/FasL在体内的作用。巨噬细胞和/或DC中携带突变型FasL或缺乏Fas、caspase-8或c-FLIP的小鼠的T细胞（Aim 3）。这项工作代表了唯一已知的人类研究？？莱姆病中的T细胞。项目叙述？？T细胞在免疫系统中仍然是一个谜。它们通常定位于上皮屏障，并被认为参与对各种感染的初始反应。事实上，保护的作用是？？T细胞已在各种感染模型中被观察到。？? T细胞也聚集在自身免疫性综合征的炎症部位，如类风湿关节炎的滑膜组织、乳糜泻的肠道或结节病的肺部。然而，关于？？的特殊性，几乎没有什么是没有的。T细胞。因此，我们在人类和老鼠身上使用莱姆病作为模型。慢性耐抗生素莱姆病患者在滑膜组织的组成、对免疫抑制剂的反应，甚至相同的HLA-DR4关联方面与自身免疫性类风湿关节炎患者在感染和潜在的自身免疫情况下的T细胞反应非常相似。该项目将寻求利用可溶性TCR-Vd1建立滑膜Vd1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它们的效应功能。理解这些相互作用将提高我们对如何？T细胞在感染和自身免疫条件下调节免疫反应。