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

KLF2 在调节 T 细胞 PD-1 表达中的关键作用

• 批准号: 10361504
• 负责人: Geoffrey S. Kansas
• 金额: $ 8万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10361504
• 关键词: Acute; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Compartmentation; Cell physiology; Cells; Data; Development; Disease; Down-Regulation; Enterobacteria phage P1 Cre recombinase; Family; Homing; Immune response; Immune system; Immunologics; Impairment; Infection; Inflammatory; Leukocytes; Lymphocytic choriomeningitis virus; Mature T-Lymphocyte; Modeling; Monoclonal Antibodies; Mus; Mutant Strains Mice; Outcome; Peripheral; Physiological; Play; Regulation; Repression; Research Personnel; Role; Signal Transduction; T cell response; T memory cell; T-Cell Activation; T-Lymphocyte; Time; Transcription Repressor; Virus Diseases; base; cell type; effector T cell; exhaust; exhaustion; gene repression; genetic approach; immune checkpoint blockade; member; migration; mouse model; novel; pathogen; programmed cell death protein 1; receptor; response; trafficking; transcription factor

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.

项目摘要/摘要 控制不同的分化，功能，迁移和生存的许多转录因子 已经确定了效应子和记忆T细胞的类别，但是其中许多的确切功能 调节免疫反应结果的转录因子未完全定义。 KLF2，a 类似克鲁诗的因子家族的成员，在免疫系统中具有多种作用，尤其是发挥作用 通过控制关键归因受体的表达来控制t（和b）细胞的迁移的关键作用 确定选择性贩运能力。 KLF2的其他功能主要是未定义的。一个 KLF2的引人注目和不寻常的特征是其在T，B和其他多种细胞类型中的表达迅速丧失 遵循细胞激活。尽管KLF2闻名了二十年来，但 几个研究者，这种KLF2损失的生理重要性仍然很差。我们有 产生了一种新颖，功能强大且复杂的鼠标模型，这是第一次成为可能的 询问KLF2下调的功能。在此模型中，KLF2表达的丢失是完全 并在任何表达或曾经表达CRE重组酶的细胞类型中永久阻塞。我们 目前的广泛数据表明，这种新型鼠标模型具有正常的外围T细胞室 在受到免疫学挑战之前，但诱导CD8 T细胞效应子响应于LCMV感染 阿姆斯特朗严重受损。此外，我们出乎意料地发现PD-1的表达是一种主要的抑制 受体是耗尽的T细胞的重要标记，是检查点阻滞的主要目标 在CD8 T细胞中，治疗较高且持续得多，与无法关闭KLF2表达的CD8 T细胞相比 WT，尽管LCMV Armstrong会引起急性解决感染，但没有 诱导T细胞耗尽。我们建议在这款新型小鼠中探索PD-1的调节和功能 模型。在AIM 1中，我们将确定PD-1信号在K121R CD8 T细胞有缺陷响应中的作用。 在AIM 2中，我们将确定KLF2是否通过抑制Blimp-1保持PD-1表达。这些 研究将大大提高我们对KLF2和KLF2下调功能的理解 细胞反应。