DEVELOPMENTAL CELL BIOLOGY OF DENDRITIC CELLS

描述(改编自调查者摘要)：树突状细胞 (DC)在免疫反应中发挥核心作用，因为它们有能力 递呈抗原，将抗原呈递给幼稚的T淋巴细胞。尽管 它们的重要性，人们对细胞生物学知之甚少， 这种高度专业化的细胞类型的发育或功能。近期 有证据表明，炎症刺激可以诱导DC 呈现出伴随着显著变化的显著发展模式 在细胞形态上，MHC-II类分子的表面表达、内吞作用和 抗原呈递能力。这些变化反映了功能 发展中国家在其生命周期的不同阶段的特征状态 哪些树突状细胞首先驻留在它们充当哨兵的周围组织中 积累但不能呈递外来抗原，然后迁移 到淋巴器官，在那里它们可以将积累的抗原呈递到 T细胞。我们现在计划确定细胞和分子机制 负责DC的成熟，并解释这些变化是如何导致的 在DC转化中形成积极参与抗原积聚的细胞 到唯一适合抗原呈递的细胞。应用程序 提出了四个具体目标：1.详细描述这三个方面 小鼠骨髓来源树突状细胞发育的不同阶段 DC，并将这些结果推广到从CD34+前体细胞培养的人DC 既是为了概括我们的结论，也是为了为 生化分析。2.研究沙门氏菌的特征和生物发生 DC中新的含有MHC II类的隔室，包括隔室 可能参与抗原处理以及独特的DC特异性 未知功能的隔室(例如，Birbeck颗粒)。3.至 阐明MHC-II类分子表面表达的调控机制 树突状细胞发育过程中的分子和各种辅助蛋白。在这种情况下 在第二类分子中，初步表明发育调节的 不变链的裂解在控制II类中起着关键作用 通过控制第II类分子的细胞内转运来表达。 DC发育的改变与抗原的调节相关 由DC进行处理和演示。该应用程序将调查如何 第二类转运、内吞作用和辅助分子的调节 表达决定了抗原的加工和提呈活动。

DESCRIPTION (Adapted from the Investigator's abstract): Dendritic cells (DCs) play a central role in the immune response due to their capacity for presenting antigens to present antigens to naive T-lymphocytes. Despite their importance, relatively little is known concerning the cell biology, development, or functions of this highly specialized cell type. Recent evidence has demonstrated that DCs can be induced by inflammatory stimuli to exhibit a remarkable developmental pattern accompanied by striking changes in cell morphology, surface expression of MHC class II, endocytosis, and the capacity for antigen presentation. These changes reflect the functional states characteristic of DCs at different stages of their life cycle, during which DCs first reside in peripheral tissues where they act as sentinels that accumulate but are unable to present foreign antigens, and then migrate to lymphoid organs where they can present their accumulated antigens to T-cells. We now plan to determine the cellular and molecular mechanisms responsible for DC maturation, and to elucidate how these alterations result in the conversion of DCs form cells actively engaged in antigen accumulation to cells uniquely well adapted for antigen presentation. The application proposes four Specific Aims: 1. To characterize in detail the three distinct stages in dendritic cell development in mouse bone marrow-derived DCs, and to extend these results to human DCs cultured from CD34+ precursors both to generalize our conclusions and to provide sufficient material for biochemical analysis. 2. To characterize the features and biogenesis of novel MHC class II-containing compartments in DCs, including compartment likely to be involved in antigen processing as well as unique, DC-specific compartments of no known function (e.g., Birbeck granules). 3. To elucidate the mechanisms controlling the surface expression of MHC class II molecules and various accessory proteins during DC development. In the case of class II molecules, initial suggest that the developmentally regulated cleavage of invariant chain plays a key role in controlling class II expression by controlling the intracellular transport of class II. 4. To correlate alterations in DC development with the regulation of antigen processing and presentation by DCs. The application will investigate how the regulation of class II transport, endocytosis, and accessory molecule expression determine antigen processing and presentation activities.