NK T Cell Interactions with NK cells during Viral Infection

描述（由申请人提供）：自然杀伤T细胞是T淋巴细胞的一个独特的亚群，可以快速产生Th1和Th2细胞因子，最显著的是IFN-y和IL-4。NK T细胞是CD4+CD8”或双阴性，依赖于非经典的、非多态性的MHC l类分子CD1d来进行阳性选择、抗原呈递和激活。使用合成配体a-半乳糖神经酰胺（a- GalCer），我们发现NK细胞的最佳NK T细胞激活需要功能性IFN-y信号。NK T细胞与NK细胞间的相互作用是间接的，由巨噬细胞和树突状细胞介导。为了确定NK T细胞和NK细胞之间是否在生理刺激中发生串扰，我们使用了小鼠巨细胞病毒（MCMV）。这种病毒在小鼠肝脏中复制，肝脏是一个特别富含NK细胞和NK T细胞的器官，其特点是肝细胞上CD1d的高表达。在MCMV感染后，我们已经证明NK T细胞以STAT1依赖的方式先于NK细胞感知病毒感染，随后扩增并合成细胞因子。这种NK T细胞的早期激活对感染的先天和适应性免疫反应的质量都有影响。重要的是，我们发现CD8+ T细胞对MCMV的反应在NK T细胞缺陷动物中受损。因此，我们在第一个特定目标中提出定义导致NK T细胞活化NK细胞的分子和细胞机制。在第二个目标中，我们建议确定NK T细胞对MCMV感染的先天和适应性免疫反应的贡献。在第三个目标中，我们建议定义a- galcer佐剂特性，并在生理刺激的背景下检查其对NK T细胞状态的长期影响。我们认为NK T细胞活化在形成先天和适应性免疫应答病原体方面具有深远的影响。本文提出的新研究将深入了解NK T细胞在病毒感染中的作用，并可能为操纵这一重要类型的免疫细胞反应提供策略。

DESCRIPTION (provided by applicant): Natural killer T cells are a unique subset of T lymphocytes that rapidly produce Th1 and Th2 cytokines, most notably IFN-y and IL-4. NK T cells are CD4+CD8" or double negative and are dependent on a non-classical, non-polymorphic MHC class l-like molecule, CD1d, for positive selection, antigen presentation, and activation. Using the synthetic ligand, a-galactosylceramide (a- GalCer), we found that optimal NK T cell activation of NK cells requires a functional IFN-y signaling. The cross-talk between NK T cells and NK cells is indirect and mediated by macrophages and dendritic cells. To determine whether a cross-talk between NK T cells and NK cells occurs during a physiological stimulus, we used the murine cytomegalovirus (MCMV). This virus replicates in the murine liver, an organ particularly rich in NK cells and NK T cells as well as being characterized by high CD1d expression on hepatocytes. Upon MCMV infection, we have shown that NK T cells sense viral infection prior to NK cells in a STAT1 dependent manner and subsequently expand and synthesize cytokines. This early activation of NK T cells has an impact on the quality of both the innate and adaptive immune responses to the infection. Importantly, we found that the CD8+ T cell response to MCMV is impaired in NK T cell deficient animals. We therefore propose in the first Specific Aim to define the molecular and cellular mechanisms that lead to NK T cell activation of NK cells. In the second Aim, we propose to determine the NK T cell contribution to the innate and adaptive immune response to MCMV infection. In the third Aim, we propose to define a-GalCer adjuvant properties and to examine its long-term effects on NK T cell status in the context of a physiological stimulus. We believe that NK T cell activation has profound consequences in shaping both the innate and the adaptive immune response to pathogens. The novel studies proposed here will provide insight into the role of NK T cells during viral infection and may provide strategies for the manipulation of this important category of immune cell responses.