Deciphering the function of CREB in regulatory T cells - regulator for type one versus type two immune-responses?

调节性T （Treg）细胞是预防自身免疫性疾病和维持免疫稳态的重要细胞之一。促进Treg细胞分化的潜在机制具有极大的治疗重要性，因此是一个深入研究的问题。先前的研究描述了转录激活因子CREB通过直接转录机制诱导Treg细胞的产生并促进其维持。与目前的模式相反，我们发现Foxp3阳性细胞中CREB的体内消耗会增强Treg细胞的频率和功能。这进一步涉及诱导CREM表达，这是一种与系统性红斑狼疮（SLE）相关的转录因子，与CREB具有相同的结合位点。特别是，Foxp3特异性缺失CREB诱导Tregs中的IL-10、IL-13和ST-2，在实验性转移性结肠炎模型中阻止炎症的发生，同时诱导IgE水平升高的活化B细胞的自发发生。因此，我们假设CREB描述了Foxp3调控的未知机制，并将在三个具体目标中揭示CREB在treg表达和功能中的作用：1。CREB如何调控Tregs的表达和功能？CREM和CREB的相互作用是否对Treg细胞的数量和功能至关重要？CREB在人类treg中的表达是如何调控的，这是否有转录和功能上的影响？我们将详细研究哪些CRE基序被CREB占据，以及DNA甲基化是否在稳态和炎症的调节性T细胞中受到影响，我们将使用实验性转移性结肠炎模型来描述CREB缺陷Tregs是否具有Th2易感性。CREM和CREB的相互作用是否对使用CRE-lox系统的treg中的IL-10调节至关重要，以及CREB缺陷小鼠中treg的更高功能是否依赖于IL-10。最后，我们将调查SLE患者、过敏性哮喘患者和炎症性肠病患者的Tregs，以及对照组的CREB/pCREB表达和随后的功能后果。对这些机制的深入了解可能有助于阐明自身免疫性疾病中T细胞耐受性破坏的原因，但也可能提供新的治疗策略，以增强自身免疫性疾病中Treg细胞的功能和/或数量。

Regulatory T (Treg) cells are one of the most important players to prevent autoimmune disease and maintain immune homeostasis. The underlying mechanisms, which promote differentiation of Treg cells, are of utmost therapeutic importance and therefore a matter of intensive research. Previous studies describe that the transcriptional activator CREB induces generation and promotes maintenance of Treg cells by direct transcriptional mechanisms. In contrast to the current paradigm, we found that in vivo- depletion of CREB in Foxp3 positive cells enhances Treg cell frequencies and function. This furthermore involved induction of CREM expression, a transcription factor, which is associated with systemic lupus erythematosus (SLE) and shares the same binding site with CREB. In particular, Foxp3 specific deletion of CREB induced IL-10 as well as IL-13 and ST-2 in Tregs, which prevented the occurrence of inflammation in a model of experimental transfer colitis, while it induced spontaneous occurrence of activated B cells with elevated IgE levels. We thus hypothesize that CREB depicts unknown mechanisms of Foxp3 regulation and will unravel the role of CREB for expression and function of Tregs in 3 specific aims: 1. How does CREB regulate expression and function of Tregs?2. Is the interaction of CREM and CREB critical for Treg cell number and function?3. How is the expression of CREB regulated in human Tregs and does this have transcriptional and functional consequences?In detail we will investigate which CRE motifs are occupied by CREB and whether DNA methylation is affected in regulatory T cells in steady state and in inflammation using a model of experimental transfer colitis, we will delineate whether CREB deficient Tregs are Th2 prone using an OVA-induced Asthma model, whether the interaction of CREM and CREB is critical for the IL-10 regulation in Tregs using the CRE-lox system and whether the higher functionality of Tregs in CREB deficient mice is dependent on IL-10. Finally we will investigate Tregs of SLE patients, of patients with allergic asthma and of patients with inflammatory bowel disease as well as controls with regard to CREB/pCREB expression and subsequent functional consequences. A deeper understanding of these mechanisms might help to elucidate the reasons for the breakdown of T cell tolerance in autoimmune diseases but might also provide new treatment strategies to enhance function and/or numbers of Treg cells in autoimmune diseases.