NK AND T CELL COSTIMULATION BY NKG2D/DAP10

描述：（改编自申请人摘要）NK细胞和CD 8+、CD 8 + T细胞 细胞抗原受体（TcR）+ T淋巴细胞（CTL）是细胞毒性淋巴细胞， 识别主要组织相容性复合体I类抗原 抗原呈递细胞和其他组织。而CTL表达TcR， 识别与肽抗原结合的经典MHC I类分子， 细胞和CTL表达Ly 49的非重排受体（在啮齿动物中），或 杀伤细胞Ig-受体（KIR）家族也与经典MHC I类结合 配体和激活或抑制效应子功能。另一种NK受体 命名为NKG 2D的C型凝集素样超家族的成员存在于 基本上所有NK细胞、CD 8+、γ-TcR + T淋巴细胞和γ-TcR + T淋巴细胞 细胞，不像KIR和Ly 49，它们表达在次要的重叠亚群上， NK细胞和记忆T细胞。NKG 2D的膜表达需要其 与信号传导衔接子分子DAP 10非共价缔合。的 NKG 2D-DAP 1 O复合物与人非经典MHC分子云母和 MICB.在人类中云母/B在正常组织中表达最低，但大量表达 由转化细胞表达，包括卵巢、乳腺、宫颈和 前列腺癌云母/B的小鼠同源物尚未鉴定。的 该计划的具体目标是：1）确定结构和功能， NKG 2D-DAPI 0受体复合物及其与其它活化和 抑制性NK细胞受体，2）确定NKG 2D-DAP 1 0的作用 受体在人和小鼠T细胞活化中的作用，3）鉴定和 表征小鼠中的功能性NKG 2D配体，以及4）生成 NKG 2D缺陷小鼠，以确定该受体在NK细胞中的生理作用 细胞和CD 8 + T细胞发育和效应子功能。鉴于广泛的 云母/B在新鲜分离的人肿瘤上的分布， NKG 2D-DAP 10受体可能为免疫调节提供新的机会 干预癌症。

DESCRIPTION: (Adapted from applicant's abstract) NK cells and CD8+, alphabeta-T cell antigen receptor (TcR)+ T lymphocytes (CTL) are cytotoxic lymphocytes that recognize major histocompatibility complex class I antigens on antigen-presenting cells and other tissues. While CTL express TcR that recognize classical MHC class I molecules bound to peptide antigens, both NK cells and CTL express non-rearranging receptors of the Ly49 (in rodents) or killer cell ig-receptor (KIR) family that also bind to classical MHC class I ligands and either activate or inhibit effector function. Another NK receptor of the C-type lectin-like superfamily, designated NKG2D, is present on essentially all NK cells, CD8+, alphabeta-TcR+ T lymphocytes, and ysigma-TcR+ T cells, unlike KIR and Ly49 that are expressed on minor overlapping subsets of NK cells and only memory T cells. Membrane expression of NKG2D requires its non-covalent association with the signaling adaptor molecule DAP10. The NKG2D-DAP1O complex binds to the human non-classical MHC molecules, MICA and MICB. In humans MICA/B is minimally expressed on normal tissues, but abundantly expressed by transformed cells, including ovarian, breast, cervical, and prostate carcinomas. Mouse homologs of MICA/B have not been identified. The specific aims of this program are: 1) to define the structure and function of the NKG2D-DAPI0 receptor complex and its relationship with other activating and inhibitory NK cell receptors, 2) To determine the role of NKG2D-DAP1 0 receptors in the activation of human and mouse T cells, 3) to identify and characterize a functional NKG2D ligand in mice and 4) to generate NKG2D-deficient mice to determine the physiological role of this receptor in NK cell and CD8+ T cell development and effector function. Given the broad distribution of MICA/B on freshly isolated human tumors, studies of the NKG2D-DAP10 receptor may provide new opportunities for immunotherapeutic intervention in cancer.