Defining the Effector T cell KLF2 Transcriptome

定义效应 T 细胞 KLF2 转录组

• 批准号: 10132700
• 负责人: Geoffrey S. Kansas
• 金额: $ 19.9万
• 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: 2021-04-12 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10132700
• 关键词: ATAC-seq; B-Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Compartmentation; Cell physiology; Cells; Chromatin; Data; Defect; Development; Disease; Down-Regulation; Effector Cell; Enterobacteria phage P1 Cre recombinase; Epigenetic Process; Failure; Family; Gene Expression; Generations; Genes; Genetic Transcription; Helper-Inducer T-Lymphocyte; Homing; Immune response; Immune system; Immunologics; Impairment; Infection; Infectious Agent; Inflammatory; Leukocytes; Lymphocytic choriomeningitis virus; Mature T-Lymphocyte; Metabolism; Modeling; Mutant Strains Mice; Outcome; Peripheral; Physiological; Play; Research Personnel; Role; T cell response; T-Lymphocyte; Time; Transcriptional Activation; adaptive immune response; arm; cell type; effector T cell; member; migration; mouse model; novel; pathogen; programs; receptor; response; trafficking; transcription factor; transcriptome; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT Transcriptional programs which control the activation, differentiation and migration of T and B lymphocytes have been studied for decades, yet remain incompletely understood. “Master” transcription factors which drive the differentiation of different classes of CD4 helper cells and CD8 effector cells have been well characterized, but functions of other transcription factors which regulate the outcome of an immune response are less well 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 almost two decades, the physiologic importance of this loss of KLF2 remains poorly defined, despite efforts by several investigators. 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 both CD4 and CD8 T cell effectors in response to infection with LCMV is sharply impaired. Using this powerful and novel mouse model, we propose to identify the transcriptional and epigenetic basis underlying defects in the generation of effector T cells associated with failure to turn off KLF2 expression. In Aim 1, we will identify aspects of T cell effector development which require loss of KLF2 expression, focusing on possible defects in defective or dysregulated activation, proliferation, or survival, and alterations in cellular metabolism or traffic. In Aim 2, we will use RNAseq and ATACseq to identify how the transcriptome and regulome of effector CD4 and CD8 T cells changes as a result of failure to extinguish KLF2 expression. These studies will greatly advance our understanding of how KLF2 controls the T cell arm of the adaptive immune response.

项目总结/文摘