DEVELOPMENTAL CELL BIOLOGY OF DENDRITIC CELLS

树突状细胞的发育细胞生物学

• 批准号: 7261323
• 负责人: IRA S MELLMAN
• 金额: $ 34.88万
• 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 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7261323
• 关键词: DEVELOPMENTAL; CELL; BIOLOGY; DENDRITIC; CELLS

Macrophages, granulocytes, many lymphocytes, and certain epithelia all express receptors for the Fc domain of IgG. Fc receptors (FcR) serve diverse functions in cellular and humoral immunity. In macrophages, they mediate the endocytosis soluble antibody-antigen complexes, the phagocytosis of large IgG-coated particles, and the release of potent cytotoxic and inflammatory agents. FcR on B-lymphocytes, on the other hand, regulate the process of B-cell activation via surface Ig. Recently, this diversity in function has been found to reflect an even greater diversity in structure. FcR comprise a large, multi-gene family of Ig-related molecules. Among the most important of these if FcRII, a receptor class expressed on virtually all FcR-positive cells. However, even this single class exhibits considerable structural heterogeneity due to cell type-specific alternative mRNA splicing that generates receptors with different cytoplasmic domains. In murine cells, the major splice products are mFcRII-B1 (lymphocytes) and -B2 (macrophages). These isoforms are identical except for an in-frame insertion of 47 amino acids in the cytoplasmic tail of mFcRII-B1. Over the past few years, we have begun to establish the functional differences between mFcRII-B1 and -B2, and to determine whether different receptor activities are associated with distinct regions of the FcRII cytoplasmic domain. For example, the presence of the insertion completely blocks endocytosis by preventing receptor accumulation at coated pits. In this proposal, we will extend these investigations using a combination of biochemical, molecular, morphological, and genetic approaches. First, we will better define the unique features of the FcRII-B2 coated pit localization domain. Although coated pit accumulation involves a conserved tyrosine-containing region of the receptor's cytoplasmic tail, more detailed analysis is required since unlike most other plasma membrane receptors the tyrosine residue itself is not required for coated pit localization in all cell types. Using molecular and biophysical approaches, the FcRII coated pit domain will be precisely defined and compared to more "conventional" coated pit domains. Second, we will define the mechanism by which the alternatively spliced insertion in mFcRII-B1 (and its human homolog) prevents coated pit localization. Preliminary evidence suggests that the insertion functions by actively preventing coated pit entry, perhaps by binding the receptor to the cytoskeleton. Third, we will define the domains involved in the regulation of B-cell activation. The role of tyrosine phosphorylation will be evaluated since this domain appears to overlap with the region required for coated pit localization, and its tyrosine falls within a consensus tyrosine phosphorylation site. Fourth, we will identify sequences required for FcRII-mediated phagocytosis and signal transduction in transfected fibroblasts and macrophage lines. Finally, we will develop the use of a genetically manipulable professional phagocyte, Dictyostelium discoideum, as a genetic system for the study of phagocytosis in general and FcRII function in particular.

巨噬细胞、粒细胞、许多淋巴细胞和某些上皮细胞， 表达IgG Fc结构域的受体。 Fc受体（FcR） 在细胞免疫和体液免疫中具有多种功能。 在巨噬细胞中， 介导内吞可溶性抗体-抗原复合物， 大IgG包被颗粒的吞噬作用，以及有效的 细胞毒性剂和炎性剂。 B淋巴细胞上的FcR，另一方面 另一方面，通过表面IG调节B细胞活化过程。 最近，人们发现这种功能的多样性反映了一种均匀的 结构更加多样化。 FcR包括一个大的多基因家族 免疫球蛋白相关的分子 其中最重要的是，如果FcRII， 几乎所有的FcR阳性细胞上都表达了这类受体。 然而，在这方面， 即使这一单一类别也表现出相当大的结构异质性， 细胞类型特异性mRNA剪接产生受体 不同的胞质结构域 在鼠细胞中， 产物是mFcRII-B1（淋巴细胞）和-B2（巨噬细胞）。 这些 同种型除了在读框内插入47个氨基酸外是相同的 在mFcRII-B1的胞质尾区。 在过去的几年里，我们已经开始建立功能 mFcRII-B1和-B2之间的差异，并确定是否不同 受体活性与FcRII的不同区域相关 胞质结构域 例如，插入物的存在 通过阻止受体聚集，完全阻断内吞作用。 有涂层的凹坑 在本提案中，我们将使用 生物化学、分子学、形态学和遗传学的结合 接近。 首先，我们将更好地定义 FcRII-B2包被的凹坑定位结构域。 虽然被膜坑 积累涉及一个保守的含酪氨酸的区域， 受体的胞质尾，需要更详细的分析，因为 与大多数其他质膜受体不同，酪氨酸残基本身 并不是所有细胞类型中的包被小凹定位所必需的。 使用 通过分子和生物物理学方法，FcRII包被的小窝结构域将 被精确定义并与更“传统”的涂层坑进行比较 域. 第二，我们将定义一种机制， mFcRII-B1（及其人同源物）中的剪接插入阻止了包被的 纹孔定位 初步证据显示 通过主动防止涂层凹坑进入，可能通过结合 细胞骨架的受体。 第三，我们将定义所涉及的领域 在调节B细胞活化中的作用 酪氨酸的作用 将评估磷酸化，因为该结构域似乎重叠 与被膜小凹定位所需的区域，及其酪氨酸 福尔斯落入共有酪氨酸磷酸化位点。 四是 鉴定FcRII介导吞噬作用和信号传导所需的序列 转染的成纤维细胞和巨噬细胞系中的转导。 最后， 我们将开发一种基因操控的专业技术， 吞噬细胞，盘基网柄藻，作为一个遗传系统的研究 和FcRII的功能。

项目成果

Presentation of exogenous antigens on major histocompatibility complex (MHC) class I and MHC class II molecules is differentially regulated during dendritic cell maturation.

在树突状细胞成熟期间，对主要组织相容性复合物（MHC）和MHC II类分子的介绍差异调节。

• DOI: 10.1084/jem.20021542
• 发表时间: 2003-07-07
• 期刊: JOURNAL OF EXPERIMENTAL MEDICINE
• 影响因子: 15.3
• 作者: Delamarre, L;Holcombe, H;Mellman, I
• 通讯作者: Mellman, I

CHMP5 is essential for late endosome function and down-regulation of receptor signaling during mouse embryogenesis.

• DOI: 10.1083/jcb.200509041
• 发表时间: 2006-03-27
• 期刊: JOURNAL OF CELL BIOLOGY
• 影响因子: 7.8
• 作者: Shim, Jae-Hyuck;Xiao, Changchun;Hayden, Matthew S;Lee, Ki-Young;Trombetta, E Sergio;Pypaert, Marc;Nara, Atsuki;Yoshimori, Tamotsu;Wilm, Bettina;Erdjument-Bromage, Hediye;Tempst, Paul;Hogan, Brigid L M;Mellman, Ira;Ghosh, Sankar
• 通讯作者: Ghosh, Sankar

Monocyte-derived dendritic cells exhibit increased levels of lysosomal proteolysis as compared to other human dendritic cell populations.

• DOI: 10.1371/journal.pone.0011949
• 发表时间: 2010-08-02
• 期刊: PloS one
• 影响因子: 3.7
• 作者: McCurley N;Mellman I
• 通讯作者: Mellman I

Maturation modulates caspase-1-independent responses of dendritic cells to Anthrax lethal toxin.

成熟调节树突状细胞对炭疽致命毒素的独立于 caspase-1 的反应。

• DOI: 10.1111/j.1462-5822.2008.01121.x
• 发表时间: 2008
• 期刊: Cellular microbiology
• 影响因子: 3.4
• 作者: Reig,Núria;Jiang,Aimin;Couture,Rachael;Sutterwala,FayyazS;Ogura,Yasunori;Flavell,RichardA;Mellman,Ira;vanderGoot,FGisou
• 通讯作者: vanderGoot,FGisou