Chemokine Receptor CCR7 In Tissue-Specific T Cell Imprinting and Autoimmunity

组织特异性 T 细胞印记和自身免疫中的趋化因子受体 CCR7

• 批准号: 8190270
• 负责人: James J. Campbell
• 金额: $ 22.69万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8190270
• 关键词: Adoptive Transfer; Age; Antigens; Architecture; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocytes; Back; Biological Assay; Blood; Bone Marrow; Bone Marrow Cells; Cell Count; Cells; Clinical; Data; Dendritic Cells; Development; Disease; Drug Delivery Systems; Effector Cell; Embryonic Development; Engraftment; Environment; Equilibrium; Event; Exhibits; Feedback; Funding; Generations; Genetic; Graft Rejection; Homing; Human; Immune; Immune response; Immune system; Immunity; Immunization; In Vitro; Inflammation; Intervention; Knowledge; Ligands; Lymphocyte; Lymphoid; Memory; Modeling; Monitor; Mus; Organ; Organogenesis; Phase; Phenotype; Play; Population; Positioning Attribute; Proliferating; Regulatory T-Lymphocyte; Reporting; Role; Seeds; Site; Skin; Symptoms; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; Transgenic Organisms; cell behavior; cell mediated immune response; cell motility; chemokine receptor; critical period; design; immune function; immunogenicity; imprint; in vivo; interest; lymph nodes; malformation; mature animal; neglect; programs; receptor; receptor function; reconstitution; research study; response; trafficking; transcription factor; tumor; Adoptive Transfer; Age; Antigens; Architecture; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocytes; Back; Biological Assay; Blood; Bone Marrow; Bone Marrow Cells; Cell Count; Cells; Clinical; Data; Dendritic Cells; Development; Disease; Drug Delivery Systems; Effector Cell; Embryonic Development; Engraftment; Environment; Equilibrium; Event; Exhibits; Feedback; Funding; Generations; Genetic; Graft Rejection; Homing; Human; Immune; Immune response; Immune system; Immunity; Immunization; In Vitro; Inflammation; Intervention; Knowledge; Ligands; Lymphocyte; Lymphoid; Memory; Modeling; Monitor; Mus; Organ; Organogenesis; Phase; Phenotype; Play; Population; Positioning Attribute; Proliferating; Regulatory T-Lymphocyte; Reporting; Role; Seeds; Site; Skin; Symptoms; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; Transgenic Organisms; cell behavior; cell mediated immune response; cell motility; chemokine receptor; critical period; design; immune function; immunogenicity; imprint; in vivo; interest; lymph nodes; malformation; mature animal; neglect; programs; receptor; receptor function; reconstitution; research study; response; trafficking; transcription factor; tumor

DESCRIPTION (provided by applicant): Chemokine receptor CCR7 is a key regulator of both the initiation and anamnestic phases of T cell mediated immune responses. By controlling dendritic cell (DC) and T cell movements throughout the body, CCR7 can influence the balance of T cell responses towards either immunity or tolerance. Much of our knowledge relevant to the function of this receptor comes from studies of mice genetically deficient in CCR7 itself or its ligands. CCR7-deficiency results in dramatic effects throughout the immune system. Abnormalities include a global paucity of T cells; absence of naive T cells from lymph nodes; absence of various dendritic cell (DC) subsets from lymphoid organs and an increased occurrence of autoimmune symptoms. Importantly, CCR7- deficiency results in profound morphological abnormalities of the secondary lymphoid organs. Our preliminary data demonstrate that many of the abnormalities observed in these mice are most likely secondary effects of the abnormal lymph node architecture. Thus, many effects previously attributed directly to CCR7 function are in reality caused by a paucity of lymphoid microenvironments able to support normal immune function. We believe that this new, paradigm-shifting information requires us to take a "back-to-the-drawing-board" approach to more fully understand the various roles played by CCR7 in the development of immune responses within mature animals. We propose experiments that will ask: 1) How can CCR7-/- cells participate normally in tissue- specific immune responses when their precursors are exceedingly rare in the sites believed to generate tissue- specific responses? 2) Is CCR7 truly required to influence the balance between immunity and tolerance by regulating the generation of Treg cells? Our recent findings will allow us to explore CCR7 as a potential target for clinical intervention in various human autoimmune diseases, tumor immunogenicity and graft rejection. PUBLIC HEALTH RELEVANCE: CCR7 is a receptor expressed by various cells in the immune system, and it is tough to allow these cells to interact with one another to generate an immune response. This receptor has been well studied, and mice lacking this receptor have many abnormalities in their ability to mount normal immune responses. However, we have recently discovered that many of the abnormalities associated with this receptor are actually the result of malformed lymph nodes, where immune cells interact, rather than direct results of the missing receptor. This new finding requires us to re-evaluate the role played by this receptor in immune responses, which we hope to explore if this project is funded. If the conclusions from our initial findings prove correct, drugs targeting CCR7 may be useful for treating diseased that involve an over-active immune system.

描述（由申请人提供）：趋化因子受体CCR7是T细胞介导的免疫反应的启动和吞咽阶段的关键调节剂。通过控制整个体内的树突状细胞（DC）和T细胞运动，CCR7可以影响T细胞对免疫或耐受性的平衡。我们与该受体功能有关的许多知识都来自对CCR7本身或其配体遗传缺陷的小鼠的研究。 CCR7缺乏性会在整个免疫系统中产生巨大的影响。异常包括T细胞的全球缺乏。缺乏淋巴结的天真T细胞；淋巴器官没有各种树突状细胞（DC）亚群，并且自身免疫性症状的发生增加。重要的是，CCR7缺乏会导致继发性淋巴器官的深刻形态异常。我们的初步数据表明，这些小鼠中观察到的许多异常是异常淋巴结结构的次要作用。因此，实际上，许多先前直接归因于CCR7功能的效应实际上是由于能够支持正常免疫功能的淋巴微环境缺乏。我们认为，这种新的，范式转移的信息要求我们采用“重新抽签”的方法，以更充分地了解CCR7在成熟动物内免疫反应中扮演的各种角色。我们提出的实验会提出：1）当CCR7 - / - 细胞在据信产生组织特异性反应的地点极为罕见时，CCR7 - / - 细胞如何正常参与组织特异性免疫反应？ 2）CCR7是否确实需要通过调节Treg细胞的产生来影响免疫和耐受性之间的平衡？我们最近的发现将使我们能够探索CCR7作为对各种人类自身免疫性疾病，肿瘤免疫原性和移植排斥的潜在临床干预的潜在目标。 公共卫生相关性：CCR7是免疫系统中各种细胞表达的受体，很难让这些细胞相互相互作用以产生免疫反应。该受体进行了充分的研究，缺乏该受体的小鼠具有正常免疫反应的能力异常。但是，我们最近发现，与该受体相关的许多异常实际上是畸形的淋巴结的结果，其中免疫细胞相互作用，而不是缺失受体的直接结果。这一新发现要求我们重新评估该受体在免疫反应中所扮演的角色，如果该项目获得资助，我们希望探索这一受体。如果我们最初发现的结论是正确的，则针对CCR7的药物可能对治疗涉及过度活跃免疫系统的患病有用。