Impact of early T-bet on CD8 T cell effector responses

项目摘要 了解极化T细胞反应的转录调控及其与炎症的联系 在过去的20年里，条件和对感染的抵抗力一直是免疫学的一个主要主题，并且 导致T-bet、GATA3和RoRt被确定为Th1、Th2发展的“主调节因子” 和Th17型反应。因此，T-bet促进干扰素-产生的能力 主导了我们对T-bet如何在感染环境中促进T细胞反应的理解。这是 T-bet-/-小鼠对各种细胞内感染的敏感性增加，包括 机会主义寄生虫弓形虫。在CD4+和CD8+T细胞中有很好的证据表明T细胞 激活伴随着两波T-bet表达(T-bet两步)，初始TCR- T-bet介导的诱导使T细胞对IL-12等细胞因子提供的极化信号敏感 这进一步加强了T-bet的表达和对差异化的承诺。然而，我们最近出版的 初步研究表明，在CD8+T细胞中，T-bet可能具有意想不到的作用。 大量早期T细胞激活诱导的事件包括黏附分子和 趋化因子与CD8+T细胞进入细胞周期。这些结果导致了新的假说 T-bet的早期诱导优化了最近激活的T和DC群体之间的相互作用 以促进进入细胞周期，优化扩张和获得效应器功能。 为了验证这一假设，我们将结合转录图谱来识别T-bet的早期靶点和状态 ART细胞免疫学和成像方法了解T-bet和手部的作用 初始事件中的候选对象，这些事件对于产生以下所需的效应器响应是必不可少的 对细胞内病原体的抗性。

Project Summary Understanding the transcriptional regulation of polarized T cell responses and their link to inflammatory conditions and resistance to infection has been a major theme in immunology for the last 20 years and has led to the identification of T-bet, GATA3 and RoRt as “master regulators” of the development of Th1, Th2 and Th17 type responses, respectively. As such, the ability of T-bet to promote IFN- production has dominated our appreciation of how T-bet contributes to T cell responses in the setting of infection. This is reinforced by the increased susceptibility of T-bet-/- mice to various intracellular infections, including the opportunistic parasite Toxoplasma gondii. In CD4+ and CD8+ T cells there is good evidence that T cell activation is accompanied by two waves of T-bet expression (the T-bet two step) and that the initial TCR- mediated induction of T-bet sensitizes T cells for polarizing signals provided by cytokines such as IL-12 that reinforce further T-bet expression and commitment to differentiation. However, our recent published and preliminary studies indicate that in CD8+ T cells T-bet may have an unanticipated role in controlling a myriad of early T cell activation induced events including upregulation of adhesion molecules and chemoattractants and entry of CD8+ T cells into cell cycle. These results have led to the novel hypothesis that the early induction of T-bet optimizes the interactions between recently activated T and DC populations to promote entry into the cell cycle, optimize expansion and the acquisition of effector functions. To test this hypothesis we will combine transcriptional profiling to identify early targets of T-bet with state of the art cellular immunology and imaging approaches to understand the role of T-bet and in hand candidates in the initial events that are essential for the generation of effector responses required for resistance to an intracellular pathogen.