NK T Cell Interactions with NK cells during Viral Infection

描述（由申请人提供）：自然杀伤T细胞是快速产生Th 1和Th 2细胞因子（最显著的是IFN-γ和IL-4）的T淋巴细胞的独特亚群。NK T细胞是CD 4 + CD 8-或双阴性的，并且依赖于非经典的、非多态性的MHC I类分子CD 1d进行阳性选择、抗原呈递和活化。使用合成配体α-半乳糖神经酰胺（α- GalCer），我们发现NK细胞的最佳NK T细胞活化需要功能性IFN-γ信号传导。NK T细胞和NK细胞之间的相互作用是间接的，并由巨噬细胞和树突状细胞介导。为了确定在生理刺激期间NK T细胞和NK细胞之间是否发生串扰，我们使用鼠巨细胞病毒（MCMV）。该病毒在小鼠肝脏中复制，该器官特别富含NK细胞和NK T细胞，并且特征在于肝细胞上的高CD 1d表达。在MCMV感染后，我们已经表明NK T细胞以STAT 1依赖性方式先于NK细胞感知病毒感染，随后扩增并合成细胞因子。NK T细胞的这种早期激活对感染的先天性和适应性免疫应答的质量都有影响。重要的是，我们发现，CD 8 + T细胞对MCMV的反应在NK T细胞缺陷型动物中受损。因此，我们在第一个具体目标中提出定义导致NK细胞的NK T细胞活化的分子和细胞机制。在第二个目标中，我们建议确定NK T细胞对MCMV感染的先天性和适应性免疫应答的贡献。在第三个目的中，我们提出定义α-GalCer佐剂性质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细胞活化在形成对病原体的先天性和适应性免疫应答方面具有深远的影响。本文提出的新研究将深入了解NK T细胞在病毒感染过程中的作用，并可能为操纵这一重要类别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.