NK Receptors and CD1 Roles in NK and NK T Cell Function

描述：(改编自申请者摘要)小鼠CD1分子具有 将糖脂呈递给NK T细胞的能力。NK T细胞是一种淋巴细胞亚群 它的特征是表达不变的TCR，自身反应性 CD1分子，以及快速产生大量IFNY和/或 刺激后IL-4。NK T细胞与多种疾病有关 免疫反应，包括对肿瘤、感染性病原体和 自身免疫性疾病进展的调控。我们假设CD1介导了 NK T细胞反应可能受抑制和激活NK的调节 NK T细胞表达的受体。我们建议将这种模式描述为 抑制和激活NK受体在小鼠NK T细胞和NK细胞上的表达 T细胞杂交瘤。此外，还将对一系列NK受体进行检测 它们调节CD1分子诱导的NK T细胞活化的能力，通过 将其导入NK T细胞杂交瘤。杂交瘤的特异性 具有很好的特性，刺激抗原信号的强度可以 通过操纵APC上表达的CD1的量来调节， 所用的脂多糖抗原。实验也将在小学进行 NK T细胞研究这些NK受体如何在免疫环境中发挥作用 体内和体外的反应。虽然已知NK受体与MHC发生反应 编码的I类分子，我们有一个令人惊讶的发现， NK细胞通过与CD1的相互作用而受到抑制，尽管CD1只是非常 与MHC I类分子有远亲关系。因此，有几个策略 将进行CD1结合NK受体(S)的鉴定，我们将 确定这些细胞是否作为NKT细胞的辅助受体。CD1的双重作用 作为活化分子的分子通过NK T细胞上的TCR和作为 通过NK细胞上的抑制受体抑制分子将被研究 在小鼠巨细胞病毒感染小鼠的背景下。这种病毒 在小鼠肝脏中复制，这是一个特别富含NK细胞和NK T的器官 肝细胞表面CD1分子含量较高。这些新奇的研究 将提供对NK的特异性和免疫调节作用的见解 CD1反应性NK T细胞和NK细胞上的受体，并提供策略 来调节这一重要类别的免疫细胞反应。

DESCRIPTION: (Adapted from applicant's abstract) Murine CD1 molecules have the ability to present glycolipids to NK T cell. NK T cells are a lymphocyte subset that is characterized by the expression of an invariant TCR, autoreactivity to CD1 molecules, and the ability to rapidly produce large amounts of IFNy and/or IL-4 following stimulation. NK T cells have been implicated in a variety of immune responses, including the response to tumors, infectious agents and the regulation of autoimmune disease progression. We hypothesize that CD1 mediated NK T cell responses may be regulated by the inhibitory and activating NK receptors expressed by NK T cells. We propose to characterize the pattern of expression of inhibiting and activating NK receptors on mouse NK T cells and NK T cell hybridomas. In addition, a series of NK receptors will be tested for their ability to regulate the NK T cell activation induced by CD1 molecules, by transfecting them into NK T cell hybridomas. The specificity of the hybridomas is well characterized, and the strength of the stimulating antigen signal can be regulated by manipulating the amount of CD1 expressed on the APC, the amount of lipoglycan antigen used. Experiments also will be carried out with primary NK T cells to study how these NK receptors act in the context of immune responses in vivo and in vitro. While NK receptors are known to react with MHC encoded class I molecules, we have made the surprising finding that a subset of NK cells are inhibited by interaction with CD1, although CD1 is only very distantly related to the MHC class I molecules. Therefore, several strategies will be undertaken to identify the CD1 binding NK receptor(s), and we will determine if these act as co-receptors for the NKT cell .The dual role of CD1 molecule as an activating molecule through the TCR on NK T cells and as an inhibitory molecule through an inhibitory receptor on NK cells will be studied in the context of the murine cytomegalovirus infection of mice. This virus replicates in murine liver, an organ particularly rich in NK cell and NK T cells and with high amount of CD1 molecules on hepatocytes. These novel studies will provide insights into the: specificity and immunoregulatory role of NK receptors on both CD1 reactive NK T cells and NK cells, and provide strategies for the regulation of this important category of immune cell responses.