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CCR 7是T细胞介导的免疫应答的起始和回忆期的关键调节剂。通过控制树突状细胞（DC）和T细胞在全身的运动，CCR 7可以影响T细胞对免疫或耐受反应的平衡。我们对这种受体功能的许多了解来自对CCR 7本身或其配体遗传缺陷的小鼠的研究。CCR 7缺陷导致整个免疫系统的显着影响。异常包括T细胞的总体缺乏;淋巴结中缺乏幼稚T细胞;淋巴器官中缺乏各种树突状细胞（DC）亚群以及自身免疫症状的发生增加。重要的是，CCR 7缺乏导致次级淋巴器官的严重形态异常。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结构的继发性影响。因此，许多先前直接归因于CCR 7功能的效应实际上是由能够支持正常免疫功能的淋巴微环境的缺乏引起的。我们认为，这种新的、范式转变的信息要求我们采取“回到绘图板”的方法，以更充分地了解CCR 7在成熟动物体内免疫反应发展中所起的各种作用。我们提出的实验将问：1）当CCR 7-/-细胞的前体在被认为产生组织特异性应答的位点极其罕见时，它们如何能够正常地参与组织特异性免疫应答？2)CCR 7真的需要通过调节Treg细胞的产生来影响免疫和耐受之间的平衡吗？我们最近的研究结果将使我们能够探索CCR 7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排斥反应的潜在靶点。

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.