NK and T Cell Costimulation by NKG2D/DAP10

描述(由申请人提供)：这个项目的总体目标是确定NKG2D受体在NK细胞和T细胞介导的免疫反应中的生理相关性。在以前的研究中，我们已经发现该受体参与了NK细胞介导的抗病毒和抗肿瘤免疫，并发现NKG2D在与I型自身免疫性糖尿病相关的病理过程中发挥着重要作用。在这一竞争性更新应用中，我们将致力于在肿瘤和病原体免疫和自身免疫的模型系统中确定NKG2D依赖的T细胞和NK细胞激活的机制。具体目标是：1.确定NKG2D及其配体在NOD小鼠模型中促进自身免疫性糖尿病的机制；2.建立离散细胞系中NKG2D选择性缺陷的遗传模型，并确定其对先天性和获得性免疫反应的影响；以及3.验证NKG2D在人和小鼠T细胞中的共刺激仅限于独特的T细胞亚群或激活状态的假设。目的1评价NKG2D在由NK细胞、CD8+细胞(如8.3 TCR转基因模型)和CD4+T细胞(如BDC2.5 TCR转基因模型)调节的自身免疫模型中的潜在作用。此外，我们将测试抗NKG2D单抗治疗是否会影响糖尿病以外的自身免疫表现。在目标2中，我们将在C57BL/6背景上产生一只NKG2D条件性缺陷小鼠，以检验NKG2D在抗自身抗原、肿瘤和病原体免疫中的重要作用的假设。一个重要的目标是在模型系统中确定NKG2D的功能是关键的--NKG2D是NK细胞、T细胞还是两者都需要的。具体目标3将确定为什么NKG2D不能共刺激新鲜分离的人NKG2D+T细胞或短期激活的小鼠NKG2D+T细胞，但能够有效地共刺激长期培养的人和小鼠CD8+T细胞和克隆，以及从体内经历自身免疫反应的组织中分离的CD8+T细胞。

DESCRIPTION (provided by applicant): The overall objective of this project is to determine the physiological relevance of the NKG2D receptor in NK cell-mediated and T cell-mediated immune responses. In prior studies, we have implicated this receptor in NK cell-mediated anti-viral and anti-tumor immunity, and have uncovered an important role for NKG2D in the pathology associated with type I autoimmune diabetes. In this competitive renewal application, we will focus our efforts towards defining the mechanisms of NKG2D-dependent activation of T cells and NK cells in model systems of immunity to tumors and pathogens and in autoimmunity. Specific aims are: 1. To determine the mechanisms whereby NKG2D and its ligands contribute to autoimmune diabetes in the NOD mouse model; 2. To develop genetic models for selective deficiency of NKG2D in discrete cell lineages and to determine the effects on innate and adaptive immune responses; and, 3. To test the hypothesis that NKG2D costimulation in human and mouse T cells is restricted to unique T cell subsets or activation states. Aim 1 will evaluate the potential role for NKG2D in models of autoimmunity that are regulated by NK cells, CD8+ cells (e.g. the 8.3 TcR-transgenic model), and CD4+ T cells (e.g. the BDC2.5 TcR-transgenic model). In addition, we will test whether anti-NKG2D mAb treatment can affect autoimmune manifestations other than diabetes. In aim 2 we will generate a conditionally NKG2D-deficient mouse on the C57BL/6 background in order to test the hypothesis that NKG2D is important in immunity against autoantigens, tumors and pathogens. An important goal is to determine in model systems where the function of NKG2D is critical --whether NKG2D is required in NK cells, T cells, or both cell types. Specific aim 3 will determine why NKG2D is unable to costimulate freshly isolated human NKG2D+ T cells or short-term activated mouse NKG2D+ T cells, but is able to efficiently costimulate long-term cultured human and mouse CD8+ T cells and clones, as well as CD8+ T cells isolated from tissue undergoing an autoimmune reaction in vivo.