Regulation of T cell homeostasis by IFN-gamma

在这项提议的最初资助期内，我们在开发小说方面取得了实质性进展 识别受干扰素-γ影响的T细胞稳态的特定方面的模型系统。 值得注意的是，这些研究表明，感染后产生的干扰素-伽马能够调节最初的 抗原特异性CD8 T细胞的扩增、收缩时相和T细胞获取速率 记忆特征。这些数据支撑并支持了我们对当前提案的总体假设，即 干扰素-γ是感染后T细胞内稳态的主要调节因子。在这份提案中，我们将采用 我们在前一个资助期为解决细胞和分子基础而开发的模型系统 用于干扰素-γ调节T细胞收缩。此外，我们会扩展研究范围，以解决以下交叉问题： 干扰素-α-β受体和干扰素-γ受体信号在调节CDS扩张中的作用 感染后的T细胞。我们的长期目标是了解干扰素-γ和其他信号分子如何 调节T细胞内稳态的特定方面，以便这些信息可以用来增强T细胞 对接种疫苗的反应。疫苗接种的改进将使最具成本效益和最广泛的 对传染病的防御。我们将通过以下具体目标来实现我们的长期目标： 具体目标1.确定所需干扰素-γ的时间、来源、数量和细胞靶点 调节CDST细胞收缩。 特定目的2.确定干扰素-γ是否通过P53和/或IL-18信号调节T细胞收缩。 特定目标3.确定干扰素-α-β和干扰素-γ信号在调节CDS中的需求 T细胞扩增。

During the initial funding period for this proposal, we made substantial progress in developing novel model systems to identify the specific aspects of T cell homeostasis that are influenced by IFN-gamma. Strikingly, these studies reveal that IFN-gamma produced after infection is able to regulate the initial expansion of antigen-specific CD8 T cells, the contraction phase and the rate at which T cells acquire memory characteristics. These data underlie and support our overall hypothesis for the current proposal, that that IFN-gamma is a major regulator of T cell homeostasis after infection. In this proposal, we will employ the model systems we developed in the preceding funding period to address the cellular and molecular basis for IFN-gamma regulation of T cell contraction. In addition, we will extend our studies to address the cross- talk between IFN-alpha-beta receptor and IFN-gamma receptor signaling in regulating the expansion of CDS T cells after infection. Our long-term goal is to understand how IFN-gamma and other signaling molecules regulate specific aspects of T cell homeostasis, such that this information can be used to enhance the T cell response to vaccination. Improvements in vaccination will allow the most cost effectiveand widespread defense against infectious disease. We will address our long-term goal through the following specific aims: Specific Aim 1. Determine the timing, source, quantity and cellular targets of IFN-gamma required to regulate CDST cell contraction. Specific Aim 2. Determine if IFN-gamma regulates T cell contraction through p53 and/or IL-18 signaling. Specific Aim 3. Determine the requirements for IFN-alpha-beta and IFN-gamma signaling in regulating CDS T cell expansion.