Type 1 IFN Function and Signaling in Immunity to Viruses

1型干扰素（IFN），包括IFN α和IFN β，具有有效的抗病毒作用，但也 介导广泛的免疫调节功能。这些包括更好地表征对 NK细胞和对CD8 T细胞的不完全理解的作用。有些是自相矛盾的， 控制1型IFN效应的机制，以允许在需要时获得亚群， 表征了细胞因子确实刺激信号传导通路，这取决于信号传导器 和转录激活因子（STAT）1和2，以诱导直接的抗病毒作用，但它们可以 有条件地激活所有的STATs，包括STAT4，和STAT4有助于IFN-？诱导 实验结果表明，总STAT1蛋白在细胞早期被显著诱导， 感染后的时间，并且1型IFN活化STAT4与STAT1水平负相关， 本项目拟检验1型干扰素的作用是通过调节 进入不同的细胞内信号通路，并且这种调节是必需的， 在对病毒感染的先天性和适应性免疫反应中。这项工作证明了 假设是正确的。相比之下， 在STAT4的差异表达水平和明显的 竞争与1型IFN受体结合，并且这些对健康很重要。 在这个更新应用程序中提出了实验来测试STAT作为主服务器的假设 通过增强和抑制1型IFN效应促进细胞应答的开关， STAT1和STAT4对相互信号传导通路的作用受到以下因素的影响， 其他STAT分子的后果。这将通过四个具体目标来实现 重点是NK和CD8 T细胞反应。目标1将定义STAT作为主开关的使用， 介导对1型干扰素反应性的积极和消极影响。目标2将机械地 定义调节STAT水平的途径。目的3将拓宽1型干扰素的表征 访问其他STAT。目标4将定义调节STAT水平和获得 在病毒感染期间改变1型IFN生物学功能的递送。免疫学病毒学， 生物化学和分子技术将被使用，这项工作将通过研究 暴露于细胞因子后的离体反应和淋巴细胞性脉络丛脑膜炎后的体内反应 野生型和基因改变小鼠的病毒感染。该项目承诺将继续推进 了解1型干扰素在形成对感染的免疫应答中的作用， 为细胞因子在治疗应用中的使用提供了见解。然而，更广泛地说， 确定细胞因子效应如何调节以增加有限数量基因的价值的范例。

The type 1 interferons (IFNs), including the IFNs alpha and beta, have potent antiviral effects, but also mediate a wide range of immunoregulatory functions. These include better-characterized effects on NK cells and incompletely understood effects on CD8 T cells. Some are paradoxical, and the mechanisms controlling type 1 IFN effects, to allow access to subsets when needed, are poorly characterized. The cytokines do stimulate a signaling pathway, depending on the signal transducers and activators of transcription (STAT) 1 and 2, to induce direct antiviral effects, but they can conditionally activate all of the STATs, including STAT4, and STAT4 contributes to IFN-? induction. As a result of experiments demonstrating that total STAT1 protein is dramatically induced at early times after infection, and that type 1 IFN activation of STAT4 negatively correlates with STAT1 levels, this project proposed to test the hypotheses that type 1 IFN effects are controlled by regulation of access to different intracellular signaling pathways, and that this regulation is required and delivered during innate and adaptive immune responses to viral infections. The work has proven the hypotheses to be correct. Unexpected mechanisms for the delivery of access to STAT1 as compared to STAT4 were discovered at the levels of differential expression of STAT4 and of apparent competition for binding to the type 1 IFN receptor, and these were shown to be important for health. Experiments are proposed in this renewal application to test the hypotheses that STATs act as master switches in promoting cellular responses by both enhancing and inhibiting type 1 IFN effects, and that the STAT1 and STAT4 effects on the reciprocal signaling pathway are influenced by, and have consequences for, other STAT molecules. This will be accomplished through four specific aims focusing on NK and CD8 T cell responses. Aim 1 will define the use of STATs as master switches to mediate positive and negative effects on responsiveness to type 1 IFNs. Aim 2 will mechanistically define the pathways regulating STAT levels. Aim 3 will broaden the characterization of type 1 IFN access to other STATs. Aim 4 will define the importance of modulating STAT levels and access for delivery of changing type 1 IFN biological functions during viral infection. Immunological, virological, biochemical, and molecular techniques will be used, and the work will be advanced by studies of responses ex vivo following exposure to cytokines, and in vivo following lymphocytic choriomeningitis virus infections in wild type and genetically altered mice. The project promises to continue to advance understanding of the control of type 1 IFN effects in shaping immune responses to infection, and to provide insights for use of cytokines in therapeutic applications. Even more broadly, however, it will identify paradigms for how cytokine effects are regulated to add value to a limited number of genes.