Chemokine System in DC and Lymphocyte Function

描述（由申请人提供）：树突状细胞（DC）/朗格汉斯细胞（LC; 皮肤DC）是免疫系统的哨兵。越来越多的证据 表明趋化因子及其受体是DC/LC重要决定因素 这些分子也在T细胞中发挥重要作用， B细胞功能。在过去的两年里， 集中于CC趋化因子受体6（CCR 6），CCR 7和CXCR 5及其配体， DC、T细胞和B细胞功能以及淋巴器官稳态。但 缺乏关于其他趋化因子在体内作用的信息 受体/配体在这些过程中。为了验证趋化因子 系统在体内LC/DC和T-和B-细胞功能中起重要作用，我们 已经采取了研究免疫功能丧失或获得的方法， 缺乏一种或多种这些分子的小鼠。在初步研究中，我们发现 CCR 2而不是CCR 5的缺陷导致DC生物学的明显缺陷。LC 在CCR 2缺失小鼠中，向引流淋巴结的迁移显著受损。 CCR 2基因敲除小鼠脾脏中的DC数量较低，这主要是由于 这是由于DC的CD 8 α + Th诱导亚群减少。此外，本发明还 在利什曼原虫感染诱导的重定位中， 从边缘区到T细胞区的脾DC。我们建议，这些 DC缺陷与BLC表达增加有关，BLC是一种B细胞特异性免疫抑制剂。 趋化因子，可能共同有助于惊人的B细胞生长和Th 2 我们在CCR 2缺陷小鼠中观察到的精氨酸偏向的不愈合表型 感染L.少校我们还发现了细胞凋亡活性增加的证据 在淋巴管和感染的淋巴结中，CCR 2-null，但不是 CCR 5缺失小鼠。为了验证我们的假设，并研究其机制 作为在趋化因子受体基因缺失小鼠中观察到的表型的基础， 我们提出了四个具体目标，我们将确定CCR 2 影响（1）LC/DC迁移、定位和功能;（2）APC效应物 淋巴器官中的细胞相互作用;（3） Th 1/Th 2诱导脾脏中的DC亚群;以及（4）我们将确定 CCR 2和CCR 5表达对Th 1和Th 2淋巴细胞的影响 分化与归巢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中的作用， 淋巴细胞功能，这些见解将提供新的机会/目标 用于治疗干预以抑制（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.