DC/NK interactions in human secondary lymphoid organs

描述(申请人提供)：自然杀伤细胞(NK)最初被定义为对病毒感染和肿瘤细胞的自发细胞毒性的介体。在人外周血中，大多数NK细胞可通过穿孔素介导细胞溶解。我们的初步数据显示，人类次级淋巴器官中的大多数NK细胞在激活后立即通过分泌细胞因子来进行免疫调节。在激活后的一周内，它们还成熟为外周血细胞毒性NK细胞的表型，并可能离开次级淋巴组织。 树突状细胞(DC)是启动获得性免疫的主要抗原提呈细胞，我们和其他研究小组最近发现DC能有效地激活外周血中的NK细胞。由于树突状细胞在成熟后迅速归宿到次级淋巴器官，我们的初步数据表明，它们激活了这些组织中的NK细胞，我们认为DC是T细胞反应之前激活NK细胞的主要媒介。此外，我们认为次级淋巴组织是这种早期NK激活的主要部位。在成功的免疫反应中，早期的NK激活被证明是限制病毒血症和肿瘤负担的关键。根据这些观察结果，我们建议： 1.确定最佳刺激次级淋巴器官中NK细胞的DC亚群和成熟刺激因子。我们将研究次级淋巴器官中NK细胞在体外产生的DC亚型刺激后的增殖和细胞因子的分泌，以及次级淋巴器官成熟后的DC在DC亚型特异性成熟刺激下的增殖和分泌。 2.鉴定次级淋巴器官中NK细胞成熟的DC来源信号。我们将测试DC来源的IL-15和IL-12对KIR的上调，对细胞因子分泌的诱导，以及次级淋巴器官的NK细胞的细胞毒性和迁移行为。 3.确定DC介导的NK激活在次级淋巴器官T细胞反应极化中的作用。我们将研究次级淋巴器官中NK的激活对DC成熟和同种异体反应以及EBV特异性T细胞极化的影响。

DESCRIPTION (provided by applicant): Natural killer cells (NK) have originally been defined as mediators of spontaneous cytotoxicity against virus-infected and tumor cells. In human peripheral blood the majority of NK cells can mediate cell lysis via perforin. Our preliminary data show that the majority of NK cells in human secondary lymphoid organs are immunoregulatory by secreting cytokines immediately after activation. Within one week after activation they, in addition, mature to the phenotype of peripheral blood cytotoxic NK cells and probably leave the secondary lymphoid tissues. Dendritic cells (DCs) are the primary antigen presenting cells that initiate adaptive immunity and we as well as other groups have recently demonstrated that DCs activate peripheral blood NK cells efficiently. Since DCs home rapidly to secondary lymphoid organs upon maturation and our preliminary data demonstrate that they activate NK cells in these tissues, we propose that DCs are the principal mediators of NK activation prior to T cell responses. In addition, we propose that secondary lymphoid tissues are the main site of this early NK activation. Early NK activation has been shown crucial in limiting viremia and tumor burden during successful immune responses. Based on these observations we propose to: 1. Identify DC subsets and maturation stimuli which optimally stimulate NK cells in secondary lymphoid organs. We will address proliferation and cytokine secretion of NK cells in secondary lymphoid organs after stimulation with in vitro generated DC subtypes and DCs of secondary lymphoid organs after maturation with DC subtype specific maturation stimuli. 2. Characterize DC derived signals for NK maturation in secondary lymphoid organs. We will test DC derived IL-15 and IL-12 for KIR upregulation, induction of cytokine secretion as well as cytotoxicity and migratory behavior by NK cells of secondary lymphoid organs. 3. Determine the role of DC mediated NK activation for polarization of T cell responses in secondary lymphoid organs. We will investigate the effect of NK activation in secondary lymphoid organs on DC maturation and alloreactive as well as EBV specific T cell polarization.