RECEPTORS FOR IMMUNOGLOBULIN G ON LEUKOCYTES

免疫球蛋白Fc部分的受体(FcGammaR)在大多数 造血细胞类型。通过结合抗原特异性免疫球蛋白， 它们在细胞内和细胞外之间提供了重要的联系 细胞之间的相互作用是必不可少的 非适应性(先天)和适应性防御系统。他们属于 到一个不同的膜受体家族，并介导广泛的阵列 细胞对抗体抗原复合体的反应。的多样性 这些反应是结构异质性的结果 FcGammaR，与它们胞质内结构域的差异有关，以及 存在于受体复合体内，或与受体相关联 对受体表达和信号都很重要的分子 转导。我们已经证明了低亲和力受体 自然杀伤细胞和巨噬细胞表达的免疫球蛋白(FcGammaRIIIA) 一种跨膜糖蛋白，在与配体结合时调节功能 通过转导导致细胞激活的信号来影响这些细胞。 其在中性粒细胞(FcGammaRIIIB)上的类似物，a 糖硅磷脂酰肌醇连接的分子，不存在这样的分子 功能。FcGammaRIII诱导的NK细胞活化主要取决于 关于激活酶的诱导激活。这方面的工作假说 提出了不同的专门效应器功能是由 不同的FcGammaR类型，依赖于不同的诱导 相同或不同细胞类型中的生化事件，以及 FcGammaR与其他蛋白质的相互作用在这一功能中起协同作用。 为了阐明不同类型的FcGammaR在NK中的作用 细胞、粒单核细胞和淋巴细胞，我们建议：1)识别 FcGammaRIII与NK相互作用时激活的分子 细胞及其配体，调节信号转导，以及2)分析 不同FcGammaR的功能作用及其调节机制 B淋巴细胞和粒单核细胞的表型。具体来说，我们 建议鉴定FcGammaRIII-配体上激活的激酶 有约束力的。这些酶的底物的作用，以及 磷酸酶在调控FcGGammaRIII介导的信号转导中的作用 也将被分析。发生在地球上的分子事件 髓系/单核细胞和B淋巴细胞对免疫复合物结合的影响 将研究和表达不同FcGammaR之间的相互作用 对相同的细胞类型进行解剖，以确定其相对作用 由FcGammaRII在这些细胞上扮演。这些研究预计将 导致识别出共同或不同的特征 FcGammaR的行为，以提供有关FcGammaR依赖的信息 对造血细胞的作用，并为理解奠定基础 先天系统的细胞功能的机制 辩护是受监管的。

Receptors for the Fc portion of IgG (FcgammaR) are expressed on most hematopoietic cell types. By binding antigen specific immunoglobulins, they provide an important link between the intra and extracellular compartments and are essential for the interactions between cells of the non adaptive (innate) and the adaptive systems of defense. They belong to an heterogeneous family of membrane receptors and mediate a wide array of cellular responses to antibody antigen complexes. The diversity of these responses is the result of the structural heterogeneity of the FcgammaR, related to differences in their intracytoplasmic domains, and to the presence, within the receptor complex, or receptor associated molecules that are important both for receptor expression and signal transduction. We have demonstrated that the low affinity receptor for IgG expressed on Natural Killer (NK) cells and macrophages (FcgammaRIIIA) transmembrane glycoprotein that, upon ligand binding, regulates functions of these cells by transducing signals that result in cell activation. Its counterpart on polymorphonuclear neutrophils (FcgammaRIIIB), a glycosilphosphatidylinositol linked molecule, is devoid of such functions. NK cell activation induced via FcgammaRIII primarily depends on induced activation of kinases. The working hypothesis of this proposal is that distinct specialized effector functions are mediated by different FcgammaR types, that depend on induction of distinct biochemical events in the same or different cell types, and that interactions of FcgammaR with other proteins cooperate in this function. In order to elucidate the role of the different types of FcgammaR on NK cells, myelomonocytic cells, and lymphocytes, we propose: 1) to identify those molecules that, activated upon interaction of FcgammaRIII on NK cells with its ligands, regulate signal transduction, and 2) to analyze functional role, an the mechanisms regulating them, of distinct FcgammaR types on B lymphocytes and myelomonocytic cells. Specifically, we propose to identify the kinases activated upon FcgammaRIII-ligand binding. The role of the substrates for these kinases, and of phosphatases, in controlling FcGgammaRIII-mediated signal transduction will also be analyzed. The molecular events occurring in myeloid/monocytic cells and B lymphocytes upon immune complexes binding will be studied and the interactions between different FcgammaR expressed on the same cell types will be dissected, to determine the relative role played by FcgammaRII on these cells. These studies are expected to result in the identification of common or distinctive features of behavior of FcgammaR, to provide information on FcgammaR-dependent functions on hematopoietic cells, and to pose the basis for understanding the mechanisms by which functions of cells of the innate system of defense are regulated.