MECHANISMS OF NATURAL KILLER CELL TOLERANCE

描述（由申请人提供）：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对病毒和肿瘤的初始防御，并影响随后的适应性免疫反应。为了防止无意的组织破坏，NK细胞不仅经历了一个“教育”过程，以确保它们能够耐受健康的“自我”细胞，而且还显示出适应环境影响和调节NK细胞效应反应的适应性特性。我们证明了NK细胞上的激活受体的持续参与导致诱导的低反应性（耐受性）。这些研究利用一种新型转基因小鼠（m157- tg）表达小鼠巨细胞病毒（MCMV）编码的m157蛋白（NK细胞特异性激活受体Ly49H的唯一已知配体），并在Ly49H+ NK细胞群中表现出低反应性。m157-Tg小鼠耐受Ly49H+ NK细胞的特征是，在非Ly49H激活受体刺激下，细胞因子产生和脱颗粒受损。激活受体调节NK细胞适应性反应（诱导耐受与激活）的机制尚不清楚。在这个建议中，我们将研究激活受体接合在NK细胞适应中的作用。本提案要检验的核心假设是，通过NK细胞激活受体的持续刺激改变了通过激活受体信号通路的信号转导，导致NK细胞的耐受状态而不是激活状态。该假设的具体目标将：(1)确定Ly49H参与向NK细胞传递抑制信号的机制，(2)评估来自耐受NK细胞的非Ly49H激活受体的信号变化，以及(3)确定m157/Ly49H相互作用导致NK细胞体内耐受的背景。

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.