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.

项目总结/摘要 许多转录因子控制着不同细胞的分化、功能、迁移和存活， 已经鉴定了效应和记忆T细胞的类别，但是其中许多的精确功能还不清楚。 调节免疫应答结果的转录因子尚未完全确定。KLF 2，a Kruppel样因子家族的成员，在免疫系统中具有多种作用，特别是在免疫系统中起作用。 通过控制关键归巢受体的表达在控制T（和B）细胞迁移中发挥关键作用 这决定了选择性的贩卖能力。KLF 2的其他功能大多未定义。一 KLF 2的显著和不寻常的特征是其在T、B和多种其它细胞类型中表达的快速丧失 在细胞激活之后。尽管KLF 2的这一特征已经被人们知道了二十多年， 一些研究者认为，KLF 2缺失的生理重要性仍然不明确。我们有 产生了一种新颖的，强大的，复杂的小鼠模型，这是第一次有可能 KLF 2下调的功能的询问。在该模型中，KLF 2表达的缺失完全被 并且在表达或曾经表达CRE重组酶的任何细胞类型中被永久阻断。我们 目前广泛的数据显示，这种新型小鼠模型具有正常的外周T细胞区室， 在免疫攻击之前，诱导CD 8 T细胞效应子应答LCMV感染 阿姆斯特朗严重受损。此外，我们意外地发现，PD-1的表达，一个主要的抑制因子， 受体，其是耗尽的T细胞的重要标志物和检查点阻断的主要靶点 在不能关闭KLF 2表达的CD 8 T细胞中， WT，尽管LCMV Armstrong引起急性消退性感染， 诱导T细胞耗竭。我们拟在这种新的小鼠中探索PD-1的调节和功能 模型在目的1中，我们将确定PD-1信号传导在K121 R CD 8 T细胞缺陷性应答中的作用。 在目标2中，我们将确定KLF 2是否通过抑制Blimp-1来维持PD-1表达。这些 这些研究将极大地促进我们对KLF 2的功能以及KLF 2在T细胞中下调的理解。 细胞反应。