Chemokine System in DC and Lymphocyte Function

描述(申请人提供)：树突状细胞(DC)/朗格汉斯细胞(LC； 皮肤树突状细胞)是免疫系统的哨兵。有越来越多的证据表明 提示趋化因子及其受体是DC/LC的重要决定因素 这些分子在T细胞中也扮演着重要的角色 和B细胞功能。在过去的两年里，人们非常关注 主要介绍CC趋化因子受体6(CCR6)、CCR7和CXCR5及其配体 DC、T细胞和B细胞功能，以及淋巴器官动态平衡。然而，在那里 缺乏关于其他趋化因子在体内的作用的信息 在这些过程中的受体/配体。来检验趋化因子 在活体内，系统在LC/DC和T、B细胞功能中起着重要作用 已经采取了调查免疫功能丧失或获得的方法 缺乏一种或多种这种分子的小鼠。在初步研究中，我们发现 CCR2而不是CCR5的缺失导致了DC生物学上的明显缺陷。LC CCR2基因缺失小鼠向引流淋巴结的迁移明显受损。 CCR2缺失的小鼠脾中的DC数量较少，这主要是因为 由于CD8αTHI诱导的DC亚群减少。另外， 在利什曼原虫主要感染诱导的重新定位过程中出现了障碍 脾树突状细胞从边缘带到T细胞区。我们建议这些 树突状细胞缺陷与B细胞特异性BLC表达增加有关 趋化因子可能共同作用于显著的B细胞生长和Th2 我们在CCR2缺陷小鼠中观察到的细胞因子偏向的不可愈合表型 感染了梅杰乳杆菌。我们还发现了细胞凋亡活性增加的证据。 在CCR2的淋巴通道和感染的淋巴结中-空而不是 CCR5基因缺失小鼠。来检验我们的假设，并研究其中的机制 在趋化因子受体基因缺失小鼠中观察到的表型， 我们提出了四个具体目标，我们将确定CCR2的机制(S) 影响(1)LC/DC迁移、定位和功能；(2)APC-效应器 淋巴器官中的细胞相互作用；(3)淋巴组织中细胞的定位和功能 Th1/Th2诱导脾内DC亚群；以及(4)我们将确定 CCR2和CCR5的表达对Th1和Th2淋巴细胞的影响 分化和归位。这些研究将大大促进我们的 了解趋化因子系统在调节LC/DC和 淋巴细胞功能，这些见解将提供新的机会/靶点 用于治疗干预：抑制(移植)或刺激 (癌症)免疫反应。

DESCRIPTION (provided by applicant): Dendritic cells (DC)/Langerhans cells (LC; skin DCs) are sentinels of the immune system. There is growing evidence to suggest that chemokines and their receptors are important determinants of DC/LC trafficking, and that these molecules also play a significant role in T-cell and B-cell function. Over the last two years, significant attention has been focused on CC chemokine receptor 6 (CCR6), CCR7, and CXCR5 and their ligands in DC, and T- and B-cell function, and lymphoid organ homeostasis. However, there is a paucity of information regarding the in vivo role of other chemokine receptors/ligands in these processes. To test the hypothesis that the chemokine system plays an important role in LC/DC and T- and B-cell functions in vivo, we have taken the approach of investigating the loss or gain of immune function in mice lacking one or more of these molecules. In preliminary studies, we found that deficiency of CCR2 but not CCR5 led to distinct defects in DC biology. LC migration to the draining lymph nodes in CCR2-null mice was markedly impaired. CCR2-null mice had lower numbers of DCs in the spleen and this was primarily due to a reduction in the CD8alpha+ Thi-inducing subset of DCs. Additionally, there was a block in the Leishmania major infection-induced relocalization of splenic DCs from the marginal zone to the T-cell areas. We propose that these DC defects in conjunction with increased expression of BLC, a B-cell-specific chemokine, may collectively contribute to the striking B-cell outgrowth and Th2 cytokine-biased nonhealing phenotype that we observed in CCR2-deficient mice infected with L. major. We also found evidence for increased apoptotic activity in the lymphatic channels and infected lymph nodes of CCR2-null but not CCR5-null mice. To test our hypothesis, and to investigate the mechanisms underlying the phenotypes observed in the chemokine receptor gene-deleted mice, we propose four specific aims We will determine the mechanism(s) by which CCR2 influences (1) LC/DC migration, localization and function; (2) APC-effector cell interactions in lymphoid organs; (3) the localization and function of Th1/Th2 inducing DC subsets in the spleen; and (4) we will determine if expression of CCR2 and CCR5 influence Thl and Th2 lymphocyte cell differentiation and homing. These studies will further significantly our understanding of the role of the chemokine system in regulating LC/DC and lymphocyte function, and these insights will offer new opportunities/targets for therapeutic intervention to suppress (transplantation) or stimulate (cancer) the immune response.