MECHANISMS OF NATURAL KILLER CELL TOLERANCE

描述(申请人提供)：自然杀伤(NK)细胞杀死异常细胞并产生细胞因子和趋化因子的能力使它们能够参与最初对病毒和肿瘤的防御，以及影响随后的适应性免疫反应。为了防止无意中的组织破坏，NK细胞不仅要经历一种“教育”过程，以确保它们对健康的“自身”细胞具有耐受性，而且还能表现出对环境影响的适应性，并调节NK细胞的效应器反应。我们证明，NK细胞上激活的受体的持续参与会导致诱导的低反应性(耐受)。这些研究利用了一种新型的转基因小鼠(m157-TG)，该小鼠表达了编码m157蛋白(NK细胞特异性激活受体Ly49H的唯一已知配体)的小鼠巨细胞病毒(MCMV)，并表明在Ly49H NK细胞群体中存在低反应性。在m157-TG小鼠中，耐受的Ly49H NK细胞的特征是通过非Ly49H激活受体的刺激而产生的细胞因子减少和脱颗粒。激活受体调节NK细胞适应性反应(诱导耐受与激活)的机制(S)尚不清楚。在这项建议中，我们将研究激活受体参与在NK细胞适应中的作用。这一建议中要检验的核心假设是，通过NK细胞激活受体的持续刺激通过激活受体信号通路改变信号转导，导致NK细胞的耐受状态而不是激活状态。针对这一假说的具体目的将：(1)确定Ly49H参与向NK细胞传递抑制信号的机制；(2)评估耐受NK细胞中非Ly49H激活受体的信号变化；(3)确定m157/Ly49H相互作用导致体内NK细胞耐受的背景。

DESCRIPTION (provided by applicant): The ability of natural killer (NK) cells to kill abnormal cells and produce cytokines and chemokines allows them to participate in the initial defense against viruses and tumors, as well as influence the subsequent adaptive immune response. In order to prevent inadvertent tissue destruction, NK cells not only undergo an "education" process to ensure they are tolerant to healthy "self" cells, but also display adaptive properties that respond to environmental influences and modulate NK cell effector response. We demonstrated that continuous engagement of an activating receptor on the NK cell results in an induced hyporesponsiveness (tolerance). Those studies utilized a novel transgenic mouse (m157-Tg) that expresses the murine cytomegalovirus (MCMV) encoded m157 protein (the only known ligand for the NK cell-specific activating receptor Ly49H) and demonstrated a hyporesponsiveness in the Ly49H+ NK cell population. Tolerant Ly49H+ NK cells in the m157-Tg mouse were characterized by impaired cytokine production and degranulation in response to stimulation through non-Ly49H activating receptors. The mechanism(s) by which activating receptors modulate NK cell adaptive responses (induction of tolerance versus activation) are not understood. In this proposal we will investigate the role of activating receptor engagement on NK cell adaptation. The core hypothesis to be examined in this proposal is that persistent stimulation through NK cell activating receptors alters signal transduction through the activating receptor signaling pathway, resulting in a tolerant rather than activated state of the NK cell. The specific aims to this hypothesis will (1) determine the mechanism by which Ly49H engagement delivers an inhibitory signal to NK cells, (2) evaluate signaling changes in non-Ly49H activating receptors from tolerant NK cells, and (3) define the context by which m157/Ly49H interaction results in NK cell tolerance in vivo.