The role of AP-1 family transcription factor networks in regulating Th17 cell effector identity

 描述（由申请人提供）：AP-1家族转录因子网络在调节Th 17细胞效应物特性中的作用项目概述CD 4 T细胞可以采用两种相反命运之一：辅助T细胞（Th）的命运，其专门支持感染的清除， 或调节性T细胞（Treg）的免疫应答。在Th亚群分化选择的多样性中，产生IL-17 A的炎性Th 17细胞由于其相对高水平的固有可塑性而脱颖而出。事实上，当环境条件改变时，这个亚群在正常情况下对细菌和真菌的粘膜免疫起作用，可以很容易地采用其他辅助性T细胞亚群的特征。虽然这一特征在清除感染期间可能是有利的，但在炎性疾病期间则不太有利。事实上，失调的Th 17细胞功能已经涉及许多自身免疫性疾病，包括炎性肠病、多发性硬化症、风湿性关节炎和银屑病。此外，在炎性疾病的情况下表现出的Th 17细胞可塑性倾向于呈现Th 1样特征，如IFNγ或T-bet的表达，这也与病理学增加相关。允许这种可塑性的潜在机制在很大程度上是未知的。在这方面，我们最近已经确定了几个AP-1家族转录因子， 促进与限制Th 17细胞可塑性的作用。缺乏JunB的CD 4 T细胞在体外分化期间和在炎性疾病的小鼠模型中均表现出失调的细胞因子和转录因子表达特征。特别地，JunB似乎抑制不适当的Treg和Th 1分化。在这里，我们的目标是测试的假设，JunB代表一种新的控制器的Th 17细胞效应和调节开关，作为一个看门人的Th 17细胞的可塑性。为此，在目的1中，我们将在命运定位报告小鼠的背景下使用CD 4-和Il 17 a-Cre删除器菌株进行JunB的条件性删除，以剖析JunB在不同炎性疾病和感染状况下维持Th 17细胞稳定性的需要。在目标2中，我们计划破译JunB调节Th 17稳定性的分子机制。在这方面，我们将（i）验证促进子集互变事件的JunB靶点;（ii）定义新的基因组谱系限制性元件及其通过AP-1复合物的调控模式;（iii）定义JunB支持Th 17谱系稳定性的激活和抑制作用。这种机制的洞察力是指导未来工作的关键，旨在利用Th 17细胞中的AP-1平衡，将破坏性炎症反应转化为有利的调节反应。

 DESCRIPTION (provided by applicant): The role of AP-1 family transcription factor networks in regulating Th17 cell effector identity PROJECT SUMMARY CD4 T cells can adopt one of two opposing fates: that of a helper T cell (Th) specialized in supporting the clearance of infections, or that of a regulatory T cell (Treg) that functions to attenuate immune responses. Among the diversity of Th subset differentiation options, IL-17A-producing inflammatory Th17 cells stand out as unique by virtue of their relatively high level of inherent plasticity. Indeed, this subset hat normally functions in mucosal immunity against bacteria and fungi can easily adopt features of other T helper subsets when environmental conditions change. While this feature can be advantageous during the clearance of an infection, it is less beneficial during inflammatory disease. Indeed, dysregulated Th17 cell function has been implicated in numerous autoimmune conditions, including Inflammatory Bowel Disease, Multiple Sclerosis, Rheumatoid Arthritis and Psoriasis. Moreover, Th17 cell plasticity exhibited in the context of inflammatory disease tends to take on Th1-like traits, such as expression of IFNγ or T-bet, that are also associated with increased pathology. The underlying mechanisms that permit this plasticity are largely unknown. In this regard, we have recently identified several AP-1 family transcription factors with opposing roles in promotion versus limitation of Th17 cell plasticity. CD4 T cells lacking JunB exhibit dysregulated cytokine and transcription factor expression signatures both during in vitro differentiation, and in mouse models of inflammatory disease. In particular, JunB appears to restrain inappropriate Treg and Th1 differentiation. Here, we aim to test the hypothesis that JunB represents a novel controller of Th17 cell effector and regulatory switches, serving as a gate-keeper of Th17 cell plasticity. To this end, in Aim 1 we will perform conditional deletion of JunB using CD4- and Il17a- Cre deleter strains in the context of a fate-mapping reporter mouse to dissect the requirement for JunB in maintaining Th17 cell stability in diverse inflammatory disease and infection conditions. In Aim 2, we plan to decipher the molecular mechanisms of JunB-regulated Th17 stability. In this regard, we will (i) validate the JunB targets that facilitat subset interconversion events; (ii) define novel genomic lineage restriction elements and their mode of regulation by AP-1 complexes; and (iii) define activating and repressing roles of JunB that support Th17 lineage stability. Such mechanistic insight is key to guiding future work aimed at exploiting the AP-1 balance in Th17 cells to divert damaging inflammatory responses into favorable regulatory responses.