DEVELOPMENTAL CELL BIOLOGY OF DENDRITIC CELLS

树突状细胞的发育细胞生物学

• 批准号: 6532692
• 负责人: IRA S MELLMAN
• 金额: $ 32.12万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-03-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6532692
• 关键词: MHC class II antigen; antigen presentation; cell biology; cell differentiation; dendritic cells; endocytosis; endopeptidases; flow cytometry; gene expression; hematopoietic stem cells; human tissue; intracellular transport; laboratory mouse; protease inhibitor; tissue /cell culture

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.

描述（改编自研究者摘要）：树突状细胞 (DCs)在免疫反应中发挥核心作用，因为它们具有 呈递抗原以将抗原呈递给初始T淋巴细胞。 尽管 它们的重要性，关于细胞生物学知之甚少， 这种高度特化的细胞类型的发育或功能。 最近 有证据表明，DC可以被炎性刺激诱导， 呈现出显著的发展模式，伴随着显著的变化 在细胞形态学、MHC II类表面表达、内吞作用和 抗原呈递的能力。 这些变化反映了功能 发展中国家在其生命周期不同阶段的特点， 其中DC首先驻留在外周组织中，在那里它们充当哨兵 它们聚集但不能呈递外来抗原， 转移到淋巴器官，在那里它们可以将积累的抗原呈递给 T细胞 我们现在计划确定细胞和分子机制 负责DC成熟，并阐明这些改变如何导致 在DC转化为积极参与抗原积累的细胞中， 转化为非常适合抗原呈递的细胞。 应用 提出了四个具体目标：1。 为了详细描述这三个 小鼠骨髓来源树突状细胞发育的不同阶段 DC，并将这些结果扩展到从CD34+前体培养的人DC 既要概括我们的结论，又要为我们提供足够的材料。 生化分析 2. 为了描述的特点和生物成因的 DC中新的含有MHC II类的隔室，包括隔室 可能参与抗原加工以及独特的DC特异性 没有已知功能的隔室（例如，Birbeck颗粒）。 3. 到 阐明控制MHC II类表面表达的机制 DC发育过程中的分子和各种辅助蛋白。 的情况下 第二类分子，初步表明，发育调节 不变链的断裂在控制II类中起关键作用 通过控制II类的细胞内转运来表达。 4. 到 将DC发育的改变与抗原的调节相关联 由跟单信用证处理和提交。 应用程序将调查如何 II类转运、内吞作用和辅助分子调节 表达决定抗原加工和呈递活性。