NK T Cell Interactions with NK cells during Viral Infection

描述(由申请人提供)：巨细胞病毒感染的小鼠模型已被广泛研究。越来越多的数据已经证明了NK细胞和CD8+T细胞在控制感染中的关键作用。然而，现在很明显，其他子集 许多细胞，如先天淋巴细胞，在对病毒的免疫反应中发挥着关键作用。我们最近发现了两个独特的群体，唾液腺NK细胞和非经典CD8+T细胞，它们参与了对MCMV的免疫应答。利用缺乏经典CD8+T细胞的小鼠，我们的初步数据表明，非经典CD8+T细胞亚群扩展并识别MCMV。有趣的是，这些小鼠对感染具有抵抗力，这表明非经典CD8+T细胞发挥了关键作用。我们还鉴定了宿主唾液腺中存在的一种独特的NK细胞亚群，这是MCMV潜伏期的位置。这群常驻唾液腺NK细胞的效应器功能有限，提示SMG中CMV潜伏期可能是NK细胞效应器反应不足所致。这项应用的目标是确定这些先天类细胞的性质，确定它们对MCMV感染的免疫反应的贡献，并操纵它们的反应以逆转潜伏期。我们将利用在前一个资助期开发的工具和MICE，以及来自合作者的新试剂。在具体目标1中，我们将鉴定非经典CD8+T细胞，确定它们的限制因素，并确定它们在病毒感染中的作用。在特定的目标2中，我们将检测唾液腺NK细胞缺陷或IL-10产生NK细胞缺陷的MCMV感染小鼠的免疫反应，进一步阐明这一独特的天然亚群的作用。在这个目标中，我们还将尝试逆转唾液腺NK细胞的低反应性表型。我们相信，我们对这一相对未被探索的研究领域的研究将扩大我们目前对类先天免疫细胞的了解，并为在潜伏期恢复足够的免疫功能的策略提供见解。

DESCRIPTION (provided by applicant): The mouse model of cytomegalovirus infection has been extensively studied. Accumulating data have demonstrated the critical roles of both NK cells and CD8+ T cells in the control of the infection. However, it is now clear that other subsets of cells such as innate lymphocytes play a crucial role during the immune response to viruses. We recently identified two unique populations, salivary gland NK cells and non- classical CD8+ T cells, contributing to the immune response to MCMV. Using mice deficient in classical CD8+ T cells, our preliminary data suggest that a non-classical CD8+ T cell subset expand and recognize specifically MCMV. Interestingly, these mice are resistant to the infection suggesting a critical role for the non-classical CD8+ T cells. We also characterized a unique NK cell subset present in the salivary glands of the host, a site of MCMV latency. This population of resident salivary gland NK cells has limited effector functions suggesting that CMV latency in the SMG could result from inadequate NK cell effector responses. The goal of this application is to determine the nature of these innate-like cells, determine their contributions to the immune response to MCMV infection, and manipulate their responses in order to reverse latency. We will take advantage of tools and mice developed in the previous funding period as well as new reagents from collaborators. In Specific Aim 1, we will characterize the non-classical CD8+ T cells, identify their restricting element, and determine their role during viral infection. In Specfic Aim 2, we will examine the immune response of MCMV infected mice deficient in salivary gland NK cells or deficient in IL-10 producing NK cells further elucidating the role of this unique innat subset. In this Aim, we will also attempt to reverse the hyporesponsive phenotype of salivary glands NK cells. We believe our studies on this relatively unexplored research area will expand our current knowledge of innate-like immune cells and provide insights into strategies to restore adequate immune functions during latency.