NK CELL RECEPTORS AND THEIR LIGANDS

描述：(改编自申请者的摘要)NK细胞已被牵连 在针对细胞内细菌、寄生虫、病毒和 肿瘤。激活和抑制受体之间的微妙平衡 调节这些细胞的效应器功能。抑制受体是 以免疫受体酪氨酸抑制的存在为特征的 胞质结构域中酪氨酸磷酸化的基序(ITIM) 重新招募细胞磷酸酶，例如SHP-1或SHP-2，导致一过性 使细胞失活。NK细胞的膜受体 对激活的描述不是很好。然而，其中许多激活 受体与DAP12、CD3zeta或FcERI-y接头蛋白相关。 这些是I型膜蛋白，表达为二硫键二聚体， 在细胞质区域含有免疫受体酪氨酸基序(ITAM)。 这些蛋白质被认为是适配器，而不是受体，因为它们 含有很短的可能缺乏结合能力的胞外结构域 配基。相反，这些信令适配器以非共价方式与几个 不同的配体结合受体，它们本身缺乏内在信号 容量。这个项目的目标是定义结构、配体 NK细胞表达的激活受体的特异性和功能。在……里面 具体地说，具体目标是：1)明确功能关系 在信号转导蛋白DAPI2、CD3zeta和FcERIy之间，并鉴定 它们在NK细胞中的相关受体，2)确定DAP12的作用， CD3zeta和FceRI-y在NK细胞发育和功能中的作用 缺乏这些适配蛋白，3)建立的生物学作用 CD94/NKG2A和CD94/NKG2C受体对CD94缺陷小鼠QAIB的分析 4)鉴定活化NK细胞受体的配基特异性。 以了解它们在免疫反应中的意义。这些研究 承诺为先天免疫在保护中的作用提供新的见解 对抗病原体和癌症。

DESCRIPTION: (Adapted from applicant's abstract) NK cells have been implicated in innate immunity against intracellular bacteria, parasites, viruses, and tumors. A delicate balance between activating and inhibitory receptors regulates the effector function of these cells. The inhibitory receptors are characterized by the presence of immunoreceptor tyrosine-based inhibitory motifs (ITIM) in their cytoplasmic domains that upon tyrosine phosphorylation recruit cellular phosphatases, e.g. SHP-1 or SHP-2, resulting in transient inactivation of the cells. The membrane receptors responsible for NK cell activation are less well characterized. However, many of these activating receptors are associated with DAP12, CD3zeta, or the FcERI-y adaptor proteins. These are type I membrane proteins, expressed as disulfide-bonded dimers, that contain immunoreceptor tyrosine-based motifs (ITAM) in the cytoplasmic domains. These proteins are considered adaptors, rather than receptors, because they contain very short extracellular domains that probably lack the ability to bind ligands. Rather, these signaling adaptors associate non-covalently with several different ligand-binding receptors, which themselves lack intrinsic signaling capacity. The goal of this project is to define the structure, ligand specificity, and function of the activating receptors expressed by NK cells. In particular, the specific aims are: 1) to define the functional relationship between the signaling adapter proteins DAPI2, CD3zeta, and FcERIy, and identify their associated receptors in NK cells, 2) to determine the role of DAP12, CD3zeta, and FceRI-y in NK cell development and function by the study of mice lacking these adaptor proteins, 3) to establish the biological role of the CD94/NKG2A and CD94/NKG2C receptors for Qaib by analysis of CD94-deficient mice and 4) to identify the ligand specificity of activating NK cell receptors in order to understand their significance in immune responses. These studies promise to provide new insights into the role of innate immunity in protection against pathogens and cancer.