A novel pathway of Th17/Th2 induction: The role of cAMP signaling in DC

摘要 Th2和Th17是获得性免疫的两个主要分支，参与保护性和病理性免疫 回应。他们免疫介导的病理范围包括过敏性疾病(Th2)， 克罗恩病(Th17)、多发性硬化症(Th17)和牛皮癣(Th17)。尽管引入了 在生物制品中，如抗细胞因子抗体，更有效和低成本的疗法还没有 可用。我们已经发现了一种新的调节Th2和Th17分化的途径 树突状细胞(DC)内cAMP水平。在该MPI RO1申请中，标题为： Th17/Th2诱导-cAMP信号在DC中的作用“我们建议探索潜在的 G蛋白介导的机制和信号转导：GαS(GNAS)和GαI (Gnai2)，它们分别刺激和抑制cAMP合成，可以提供基础 为这样的新疗法。抑制这一途径(低cAMP)可刺激Th2诱导DC (前Th2树突状细胞)，其激活(高cAMP)诱导Th17诱导树突状细胞(前Th17树突状细胞)。我们 产生了两种遗传性小鼠模型：GNASΔCD11c，形成自发的Th2型偏见和 产生Th17偏向反应的GNAI2ΔCD11c。我们最近确认了不同的阵营 诱导剂调节cDC2细胞中转录因子的表达水平 Th17/Th2的分化，如干扰素调节因子4(IRF4)、IRF5、Kruppel样因子4 (KLF4)和Notch2。我们在这里展示了不同的cAMP诱导剂调节表达水平。 并切换随后的Th偏向，这导致我们提出cDC2 细胞代表可塑性DC亚群，cAMP水平决定了cDC2 有支持Th17和支持Th2的偏见。因此，在本应用程序中，我们将探索和剖析 以下主题：在SA1中-我们将分析Gnai2基因缺失是否会增加cAMP 在DC中导致Th17相关免疫病理超时，在SA2中-我们将确定和 测试定义表型前Th17或前Th2 cDC2的转录网络 我们将测试GPCR激动剂(即β2AR激动剂)是否会增加 CAMP水平，引发Th17驱动的中性粒细胞哮喘，在SA4-我们将识别和 从功能上测试DC细胞产生的新型前Th17或前Th2介体。总而言之-我们的 CAMP调节CDC前Th2和前Th17诱导特性的发现导致了 Th2/Th17调节新途径的鉴定。研究结果将提供新的见解 CDC2和Th2和Th17偏向的可塑性。它有可能推动基本的 免疫学研究，为新型和创新的免疫治疗奠定基础 战略。

Abstract Th2 and Th17 are two major arms of adaptive immunity involved in protective and pathological responses. The range of their immune-mediated pathologies includes allergic diseases (Th2), Crohn’s disease (Th17), multiple sclerosis (Th17) and psoriasis (Th17). Despite the introduction of biologics such as anti-cytokines Abs, more effective and low-cost therapies are not yet available. We have identified a new pathway that regulates both Th2 and Th17 differentiation by cAMP levels in dendritic cells (DC). In this MPI RO1 application entitled: “A novel pathway of Th17/Th2 induction - the role of cAMP signaling in DC” we propose that exploring the underlying mechanisms and signaling events mediated through the G proteins; Gαs (Gnas) and Gαi (Gnai2), which stimulate and inhibit cAMP synthesis, respectively, can provide the foundation for such new therapies. The inhibition of this pathway (low cAMP) provokes Th2-inducing DC (pro-Th2 DC), and its activation (high cAMP) induces Th17-inducing DC (pro-Th17 DC). We generated two genetic mouse models; GnasΔCD11c that develop spontaneous Th2 bias and Gnai2ΔCD11c that develop a Th17 bias responses. We recently identified that different cAMP inducers regulate the expression levels of transcription factors in cDC2 cells that provoke Th17/Th2 differentiation such as interferon regulatory factor 4 (IRF4), IRF5, Kruppel-like factor 4 (KLF4) and Notch2. Here we shown that different cAMP inducers regulate the expression levels of these factors and switch the subsequent Th bias, which has led us to propose that the cDC2 cells represent a plastic DC subpopulation and that the cAMP levels dictate whether the cDC2 have a pro-Th17 and pro-Th2 bias. Hence, in this application we will explore and dissect the following topics: In SA1 - we will analyze whether increasing cAMP by genetic deletion of Gnai2 in DC causes a Th17-associated immunopathology overtime, in SA2 – we will determine and test the transcriptional network that defines the phenotypic pro-Th17 or pro-Th2 cDC2 subpopulations, in SA3 - we will test whether GPCR agonists (i.e., β2AR agonists) that increase cAMP levels, provoke Th17-driven neutrophilic asthma, and in SA4 - we will identify and functionally test novel pro-Th17 or pro-Th2 mediators produced by DC cells. In summary - our discovery that cAMP regulates the pro-Th2 and pro-Th17 inducing properties of cDCs has led to the identification of new pathway of Th2/Th17 regulation. The results will provide new insights into the plasticity of cDC2 and Th2- and Th17- biasing. It has the potential to advance basic immunological research and establish the basis for novel and innovative immunotherapeutic strategies.