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

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记忆阶段的关键调节因子。通过控制树突状细胞(DC)和T细胞在体内的运动，CCR7可以影响T细胞对免疫或耐受反应的平衡。我们关于该受体功能的大部分知识来自对CCR7本身或其配体基因缺陷的小鼠的研究。CCR7缺陷会导致整个免疫系统产生戏剧性的影响。异常包括T细胞的全球稀少；淋巴结中缺乏原始T细胞；淋巴器官中缺乏各种树突状细胞(DC)亚群；自身免疫症状的发生率增加。重要的是，CCR7缺乏导致次级淋巴器官严重的形态异常。我们的初步数据表明，在这些小鼠中观察到的许多异常很可能是异常淋巴结构的继发性影响。因此，许多以前直接归因于CCR7功能的影响实际上是由于缺乏能够支持正常免疫功能的淋巴微环境造成的。我们认为，这种新的、改变范式的信息要求我们采取“从头开始”的方法，以更充分地理解CCR7在成熟动物体内免疫反应发展中所扮演的各种角色。我们提出的实验将问：1)当CCR7-/-细胞的前体在被认为产生组织特异性反应的部位极其罕见时，它们如何正常参与组织特异性免疫反应？2)CCR7真的需要通过调节Treg细胞的生成来影响免疫和耐受之间的平衡吗？我们最近的发现将使我们能够探索CCR7作为临床干预各种人类自身免疫性疾病、肿瘤免疫原性和移植物排斥反应的潜在靶点。 与公共卫生相关：CCR7是一种由免疫系统中的各种细胞表达的受体，很难允许这些细胞相互作用以产生免疫反应。这种受体已经得到了很好的研究，缺乏这种受体的小鼠在建立正常免疫反应的能力上有许多异常。然而，我们最近发现，与该受体相关的许多异常实际上是免疫细胞相互作用的畸形淋巴结的结果，而不是该受体缺失的直接结果。这一新发现要求我们重新评估这种受体在免疫反应中所起的作用，如果这个项目得到资助，我们希望能够探索这一点。如果我们初步发现的结论被证明是正确的，针对CCR7的药物可能对治疗涉及免疫系统过度活跃的疾病有用。

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.