NK AND T CELL COSTIMULATION BY NKG2D/DAP10

描述：(改编自申请者摘要)NK细胞和CD8+、Alphabeta-T 细胞抗原受体(TCR)+T淋巴细胞(CTL)是一种细胞毒性淋巴细胞 识别主要组织相容性复合体I类抗原 抗原提呈细胞和其他组织。虽然CTL表示TCR 识别与多肽抗原结合的经典MHC I类分子，包括NK 细胞和CTL表达Ly49的非重排受体(在啮齿动物中)或 也与经典MHC-I类结合的杀伤细胞免疫球蛋白受体(KIR)家族 并激活或抑制效应器功能。另一种NK受体 C型凝集素样超家族的NKG2D存在于 基本上所有的NK细胞、CD8+、Alphabeta-TCR+T细胞和ysigma-TCR+T细胞 与KIR和Ly49不同的是，KIR和Ly49表达在 NK细胞和记忆T细胞。NKG2D的膜表达需要其 与信号转接子分子DAP10的非共价结合。这个 NKG2D-DAP1O复合体与人非经典MHC分子MICA和MICA结合 MICB。在人类中，MICA/B在正常组织中表达最少，但大量表达 由转化的细胞表达，包括卵巢、乳腺、宫颈和 前列腺癌。MICA/B的小鼠同源基因尚未被鉴定。这个 该计划的具体目标是：1)确定 NKG2D-DAPI0受体复合体及其与其他激活因子的关系 抑制性NK细胞受体，2)确定NKG2D-DAP1 0的作用 受体在人和小鼠T细胞激活中的作用，3)识别和 在小鼠中鉴定具有功能的NKG2D配体和4)产生 NKG2D基因缺陷小鼠确定该受体在NK中的生理作用 细胞和CD8+T细胞的发育和效应功能。考虑到广泛的 MICA/B在新鲜分离的人肿瘤上的分布 NKG2D-DAP10受体可能为免疫治疗提供新的机会 对癌症的干预。

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.