Critical Role for KLF2 in Regulation of PD-1 Expression in T cells

项目摘要/摘要 众多转录因子控制着不同物种的分化、功能、迁移和存活 效应器和记忆性T细胞的类别已经确定，但其中许多细胞的确切功能 调节免疫反应结果的转录因子还没有完全定义。KLF2，a Kruppel-like因子家族的成员，在免疫系统中扮演不同的角色，尤其是在 关键归巢受体在控制T(和B)细胞迁移中的关键作用 这决定了选择性贩运的能力。KLF2的其他功能大多仍未定义。一个 KLF2的显著和不同寻常的特征是它在T、B和多种其他类型的细胞中迅速失去表达 在细胞激活之后。尽管KLF2的这一特性早在二十多年前就已为人所知，而且 几位研究人员指出，KLF2基因缺失的生理意义仍不明确。我们有 产生了一种新颖、强大和复杂的鼠标模型，这首次使 KLF2下调功能的讯问。在这个模型中，KLF2的表达完全丧失 并在表达或曾经表达cre重组酶的任何细胞类型中永久阻断。我们 目前广泛的数据表明，这种新的小鼠模型具有正常的外周T细胞室 在免疫攻击之前，尚未诱导CD8T细胞效应器对LCMV感染的反应 阿姆斯特朗受到了严重的损害。此外，我们意外地发现PD-1的表达是一种主要的抑制因素 受体是耗竭T细胞的重要标志，也是检查点封锁的主要靶点 治疗，与不能关闭KLF2表达的CD8 T细胞相比，更高，更持久 WT，尽管公认的事实是LCMV阿姆斯特朗引起急性分离性感染，而不是 诱导T细胞耗尽。我们建议探索PD-1在这一新型小鼠中的调节和功能 模特。在目标1中，我们将确定PD-1信号在K121R CD8 T细胞缺陷反应中的作用。 在目标2中，我们将确定KLF2是否通过抑制Blimp-1来维持PD-1的表达。这些 研究将显著提高我们对KLF2和KLF2在T细胞中下调功能的理解 细胞反应。

PROJECT SUMMARY/ABSTRACT Numerous transcription factors which control the differentiation, function, migration and survival of different classes of effector and memory T cells have been identified, but the precise functions of many of these transcription factors which regulate the outcome of an immune response are incompletely defined. KLF2, a member of the Kruppel-like factor family, has diverse roles in the immune system, and in particular plays a critical role in controlling migration of T (and B) cells via its control of expression of key homing receptors which determine selective trafficking capabilities. Other functions of KLF2 remain mostly undefined. A striking and unusual feature of KLF2 is its rapid loss of expression in T, B and multiple other cell types following cellular activation. Despite this feature of KLF2 being known for over two decades and efforts by several investigators, the physiologic importance of this loss of KLF2 remains poorly defined. We have generated a novel, powerful, and sophisticated mouse model which for the first time makes possible interrogation of the functions of KLF2 downregulation. In this model, loss of KLF2 expression is completely and permanently blocked in any cell type which expresses or which once expressed cre recombinase. We present extensive data showing that this novel mouse model has a normal peripheral T cell compartment prior to immunologic challenge, yet induction of CD8 T cell effectors in response to infection with LCMV Armstrong is sharply impaired. In addition, we unexpectedly found that expression of PD-1, a major inhibitory receptor which is an important marker of exhausted T cells and the primary target of checkpoint blockade therapy, is higher and far more sustained in CD8 T cells which cannot turn off KLF2 expression, compared to WT, despite the well established fact that LCMV Armstrong causes acute resolving infection and does not induce T cell exhaustion. We propose to explore the regulation and function of PD-1 in this novel mouse model. In Aim 1, we will determine the role of PD-1 signaling in defective responses of K121R CD8 T cells. In Aim 2, we will determine whether KLF2 maintains PD-1 expression via repression of Blimp-1. These studies will significantly advance our understanding of the functions of KLF2 and KLF2 downregulation in T cell responses.