Role of Bcl11b in CD4+ T cells and innate lymphoid cells

总结 第二类免疫疾病，如哮喘，过敏和慢性鼻窦炎仍然是重要的健康和 经济负担。两种免疫群体在这些疾病中发挥着关键作用，即II组先天性 淋巴样细胞（ILC2）和Th2细胞，也是抗蠕虫反应的关键。ILC2和Th2细胞具有许多 在他们的节目，包括生产II型细胞因子的共同特点。转录因子（TF） 是这些细胞程序的关键调节器，它们的功能和身份。理解转录和 调节这些细胞的表观遗传控制对于设计有效的治疗是最重要的。我们 最近发表的数据表明，Bcl11b是正常免疫过程中ILC2和Th2细胞的必需TF。 反应和致病条件下，特别是在促进他们的II型程序，通过控制必要的 TF和下游效应基因。此外，我们在上一个融资期公布的数据显示， Bcl11b限制IL-2和Th-2中的替代谱系程序，包括I型、III型和NK基因程序 细胞，对免疫反应和疾病结果有重大影响。引人注目的是，在致病性Th17细胞中， Bcl11b发挥对足作用，阻断Th2 TF Gata3和IL 4基因表达，支持以下概念： bcl11b在维持谱系身份方面是必不可少的，并且以依赖于上下文的方式运作。在下一个周期中 我们建议研究Bcl11b调节ILC2中II型反应的机制， 辅助细胞使用人ILC2s和Th2细胞，以及小鼠在II型免疫应答和疾病背景下 模型我们将建立Bcl11b如何促进II型程序和限制替代谱系程序。我们 我建议描述常见的调节因子和调节分子机制的差异 IL 2和Th2细胞中的Bcl 11b介导。我们将研究Bcl11b如何发挥其细胞特异性作用， 与谱系特异性TF和染色质修饰剂以及特异性增强子和沉默子上的重塑剂一起， 产生足够的表观遗传状态以表达或沉默必需的程序基因。另外我们 将确定Bcl11b是否控制局部染色质循环，以防止或允许细胞特异性 增强剂和消音剂。在这些研究结束时，我们将有一个平台来了解 小鼠和人类ILC2和Th2程序的分子组成部分，以及转录和表观遗传 正常和疾病状态下的调节机制，这将有助于更好地了解疾病， 未来的优化治疗

Summary Type two immune diseases such as asthma, allergies and chronic rhinosinusitis remain important health and economical burdens. Two immune populations play critical roles in these diseases, namely Group II innate lymphoid cells (ILC2s) and Th2 cells, also critical in anti-helminth responses. ILC2s and Th2 cells have numerous common characteristics in their programs, including production of type II cytokines. Transcription factors (TFs) are key regulators for these cell programs, their functioning and identity. Understanding transcriptional and epigenetic control regulating these cells is of the highest importance for designing efficient treatments. Our recently published data show that Bcl11b is an essential TF for both ILC2 and Th2 cells during normal immune responses and in pathogenic conditions, specifically in promoting their type II program, by controlling essential TFs and downstream effector genes. In addition, our published data in the previous funding period showed that Bcl11b restricts alternate lineage programs, including type I, type III and NK gene programs in ILC2s and Th2 cells, with major impact on the immune responses and disease outcome. Strikingly, in pathogenic Th17 cells, Bcl11b plays an antipodal role, blocking the Th2 TF Gata3 and IL4 gene expression, supporting the concept that Bcl11b is essential in maintaining lineage identity and operates in a context dependent manner. In the next cycle of funding we propose to investigate the mechanisms by which Bcl11b regulates type II response in ILC2s and Thelper cells using human ILC2s and Th2 cells, and mice in the context of type II immune responses and disease models. We will establish how Bcl11b promotes type II program and restricts alternate lineage programs. We propose to delineate the common denominators and the differences in the molecular mechanisms of regulation mediated by Bcl11b in ILC2s and Th2 cells. We will investigate how Bcl11b exerts its cell specific roles by working with lineage specific TFs and chromatin modifiers and remodelers on specific enhancers and silencers to generate the adequate epigenetic status for expression or silencing of essential program genes. In addition, we will determine whether Bcl11b controls local chromatin looping to prevent or allow activity of cell specific enhancers and silencers. At the conclusion of these studies, we will have a platform for understanding the molecular components of the ILC2 and Th2 programs in mice and humans and the transcriptional and epigenetic regulatory mechanisms in normal and disease states, which will serve for better understanding of disease and future optimized treatments.