Role of IRF4 in T helper cell fate decisions

IRF4 在 T 辅助细胞命运决定中的作用

• 批准号: 8836931
• 负责人: Roger Sciammas
• 金额: $ 38.8万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8836931
• 关键词: Address; Affinity; Antibody Response; Antigens; Area; Avidity; B-Lymphocytes; Blood; CD4 Positive T Lymphocytes; Cell physiology; Cells; Data; Distal; Epithelial; Feedback; Fibrinogen; Frequencies; Future; Gene Expression Regulation; Generations; Genetic; Genome; Genomics; Goals; HIV; HIV vaccine; Helper-Inducer T-Lymphocyte; IRF4 gene; Immune; Immune response; Knowledge; Ligands; Lymphoid Tissue; Measures; Memory; Methodology; Methods; Molecular; Nature; Outcome; Pathway interactions; Pattern; Peptide/MHC Complex; Peptides; Plasma Cells; Play; Preventive Medicine; Public Health; Receptor Signaling; Regulation; Regulator Genes; Role; Side; Signal Transduction; Solid; Specific qualifier value; Structure of germinal center of lymph node; System; T-Lymphocyte; Testing; Th1 Cells; Thinking; Time; Tissues; Transgenic Mice; Vaccine Antigen; Vaccines; Variant; Vertebral column; Viral; base; cell type; cytokine; gene repression; improved; in vivo; in vivo Model; innovation; insight; microbicide; mouse model; neutralizing antibody; novel; pathogen; public health relevance; receptor; response; success; tool; transcription factor

DESCRIPTION (provided by applicant): Well executed cell fate choices of CD4+ T helper (Th) cells into effector Th1, Th2, or Th17 which control microbicidal actions of innate immune cells or into T follicular helper (Tfh) cells which control B cell and antibody responses are essential for vaccine-elicited memory responses and immune protection. Signal regulated transcription factor networks coordinate Th cell fate decisions. The proposed studies address the central hypothesis that TCR affinity-based induction of graded IRF4 expression functions to control alternate T helper cell fate choices. It has been shown that variations in TCR affinity for pMHC play a determining role in Th cell fate choices by somehow regulating the expression of the Blimp-1/Bcl6 transcription factors, important for T effector/Tfh, respectively. The challenges that remain are to identify the TCR-proximal molecular determinants and how they function to establish the distal pattern of Blimp-1 and Bcl6 expression. Important insight comes from our recent demonstration that, in B cells, expression of IRF4 functions as a switch to apportion the frequency of Bcl6-expressing Germinal Center (GC) B cells and Blimp-1-expressing plasma cells. This pivotal function of IRF4 is due to its ability to directly activate either side of the cl6-Blimp-1 negative feedback loop depending on whether IRF4 cellular concentrations are transient/low or whether they are sustained/high, respectively. Notably, IRF4 expression dynamics is set by the intensity of B cell antigen receptor (BCR) signaling such that increased antigen affinity/avidity augments IRF4 levels. Our findings in B cells as well as our evidence that a TCR � IRF4 � Bcl6/Blimp-1 axis may operate in Th cell fate gene regulatory networks raise the possibility that TCR signal strength sets forth a dynamic of IRF4 expression that in turn functions to control the proportions of Blimp-1-expressing effector Th1 cells or Bcl6-expressing Tfh cells. We will test this hypothesis by determining the relationship between TCR signal strength and IRF4 expression dynamics in vivo (Aim 1). In Aim 2, we will determine whether TCR-induced variations in IRF4 levels correlate with outcomes in Th cell fate choice. Importantly, to establish whether observed outcomes are dependent on IRF4 expression levels (as opposed to other factors controlled by the TCR) we will use an Irf4-inducible mouse model that we developed to modulate the timing and levels of IRF4 expression. Lastly, in Aim 3, we will determine how TCR signal strength dependent control of IRF4 expression levels are wired within Th cell fate gene regulatory networks to enable appropriate Th cell fate choices. Overall, we expect to establish whether TCR- regulated dynamics of IRF4 expression functions as a Th cell fate switch. Our studies seek to reveal cell intrinsic mechanisms of Th cell fate choice that could define unique targets and strategies to enhance the efficacy of future vaccines.

描述（由适用提供）：CD4+ T助手（Th）细胞（TH1，TH2或TH17）控制的细胞命运选择良好，控制了先天性免疫电池的微生物作用或控制B细胞和抗体响应的微生物作用，对于疫苗 - 细胞和抗体响应是疫苗 - 细胞内存响应的必不可少的。信号调节的转录因子网络协调细胞命运决策。拟议的研究介绍了以下假设，即基于TCR亲和力的归纳IRF4表达功能以控制替代T辅助细胞脂肪的选择。已经表明，TCR亲和力的PMHC的变化通过以某种方式调节Blimp-1/Bcl6转录因子的表达，在细胞脂肪的选择中起着确定的作用，对T效应器/TFH很重要。挑战 仍然可以识别TCR-羟基分子确定剂以及它们如何功能以建立Blimp-1和Bcl6表达的独特模式。重要的见解来自我们最近的演示，即在B细胞中，IRF4的表达作用是比例分配表达Bcl6的发芽中心（GC）B细胞和表达Blimp-1表达血浆细胞的频率。 IRF4的这种关键函数是由于其能够直接激活Cl6-Blimp-1负反馈循环的两侧，具体取决于IRF4细胞浓度是短暂的/低还是持续/高。值得注意的是，IRF4表达动力学是由B细胞抗原受体（BCR）信号的强度设定的，从而增加了抗原亲和力/亲和力增加IRF4水平。我们在B细胞中的发现以及我们的证据表明 TCR-irf4-bcl6/blimp-1轴可能在细胞命运基因调节网络中起作用，这增加了TCR信号强度提出IRF4表达的动态，而IRF4表达的动态反过来又可以控制表达Blimp-1表达效应的效应子Th1细胞或表达BCL6-表达TFH TFH细胞的比例。我们将通过确定体内TCR信号强度与IRF4表达动力学之间的关系来检验这一假设（AIM 1）。在AIM 2中，我们将确定TCR诱导的IRF4水平的变化是否与细胞命运选择的结果相关。重要的是，要确定观察到的结果是否取决于IRF4表达水平（与TCR控制的其他因素相反），我们将使用IRF4诱导的小鼠模型来调节IRF4表达的时间和水平。最后，在AIM 3中，我们将确定如何在细胞命运基因调节网络中连接TCR信号强度的控制IRF4表达水平，以实现适当的TH细胞命运选择。总体而言，我们期望确定IRF4表达的TCR调节动力学是否充当细胞命运开关。我们的研究试图揭示细胞命运选择的固有机制，该机制可以定义独特的靶标和策略，以提高未来疫苗的效率。