DC/NK interactions in human secondary lymphoid organs

描述（由申请人提供）：自然杀伤细胞（NK）最初被定义为针对病毒感染细胞和肿瘤细胞的自发细胞毒性介质。在人外周血中，大多数NK细胞可以通过穿孔素介导细胞裂解。我们的初步数据表明，大多数的NK细胞在人类次级淋巴器官的免疫调节分泌细胞因子激活后立即。此外，在活化后一周内，它们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（Dendritic cells，DCs）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证实DCs能有效激活外周血NK细胞。由于DC的家迅速成熟后的次级淋巴器官和我们的初步数据表明，他们激活NK细胞在这些组织中，我们建议，DC是NK细胞激活T细胞反应之前的主要介质。此外，我们提出，次级淋巴组织是这种早期NK激活的主要部位。早期NK活化已显示在成功的免疫应答期间限制病毒血症和肿瘤负荷方面至关重要。根据这些意见，我们建议： 1.确定DC亚群和成熟刺激，最佳刺激NK细胞在次级淋巴器官。我们将讨论体外产生的DC亚型刺激后次级淋巴器官中NK细胞的增殖和细胞因子分泌，以及DC亚型特异性成熟刺激成熟后次级淋巴器官的DC。 2.表征次级淋巴器官中NK成熟的DC衍生信号。我们将测试DC衍生的IL-15和IL-12的KIR上调、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活化对次级淋巴器官中T细胞应答极化的作用。我们将研究次级淋巴器官中NK激活对DC成熟和同种异体反应性以及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.