Role of IRF4 in T helper cell fate decisions

描述（由申请方提供）：CD 4 + T辅助（Th）细胞转化为控制先天免疫细胞杀微生物作用的效应Th 1、Th 2或Th 17或转化为控制B细胞和抗体应答的T滤泡辅助（Tfh）细胞的良好执行的细胞命运选择对于疫苗引发的记忆应答和免疫保护是必需的。信号调节转录因子网络协调Th细胞命运决定。所提出的研究解决了中心假设，即基于TCR亲和力的分级IRF 4表达诱导功能控制备用T辅助细胞命运选择。已经表明，TCR对pMHC亲和力的变化通过以某种方式调节Blimp-1/Bcl 6转录因子的表达在Th细胞命运选择中起决定性作用，Blimp-1/Bcl 6转录因子分别对T效应子/Tfh很重要。的挑战 剩下的是鉴定TCR近端分子决定簇以及它们如何起作用以建立Blimp-1和Bcl 6表达的远端模式。重要的见解来自于我们最近的证明，即在B细胞中，IRF 4的表达起着开关的作用，以分配表达Bcl 6的生殖中心（GC）B细胞和表达Blimp-1的浆细胞的频率。IRF 4的这种关键功能是由于其直接激活cl 6-Blimp-1负反馈环任一侧的能力，这分别取决于IRF 4细胞浓度是瞬时/低还是持续/高。值得注意的是，IRF 4表达动力学由B细胞抗原受体（BCR）信号传导的强度设定，使得抗原亲和力/亲合力增加IRF 4水平。我们在B细胞中的发现以及我们的证据， TCR → IRF 4 → Bcl 6/Blimp-1轴可能在Th细胞命运基因调控网络中起作用，这增加了这样一种可能性，即TCR信号强度决定了IRF 4表达的动态，而IRF 4反过来又起着控制Blimp-1表达效应Th 1细胞或Bcl 6表达Tfh细胞比例的作用。我们将通过确定体内TCR信号强度与IRF 4表达动力学之间的关系来检验这一假设（目的1）。在目标2中，我们将确定TCR诱导的IRF 4水平变化是否与Th细胞命运选择结果相关。重要的是，为了确定观察到的结果是否依赖于IRF 4表达水平（与TCR控制的其他因素相反），我们将使用我们开发的IRF 4诱导型小鼠模型来调节IRF 4表达的时间和水平。最后，在目标3中，我们将确定IRF 4表达水平的TCR信号强度依赖性控制如何在Th细胞命运基因调控网络内连接，以实现适当的Th细胞命运选择。总的来说，我们期望确定IRF 4表达的TCR调节动力学是否作为Th细胞命运开关起作用。我们的研究旨在揭示Th细胞命运选择的细胞内在机制，从而确定独特的靶点和策略，以提高未来疫苗的效力。

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.