Role of the transcription factor c-Maf in controlling the development and function of RORgt+ type 3 innate lymphoid cells

近年来，人们发现先天淋巴样细胞（ILCs）作为一种新的组织淋巴细胞亚家族，通过控制宿主-微生物群相互作用、增强适应性免疫和调节组织炎症等多种免疫途径发挥作用。重要的是，ILCs的功能也超越了传统的免疫学，延伸到代谢稳态或组织重塑。鉴于这种多方面的功能，鉴定控制ILC发育和功能的分子途径对于更好地理解其生物学以及开发新的策略来操纵这些细胞是至关重要的。一般来说，ilc根据其主转录因子的使用和细胞因子的产生能力分为三个亚群。这些子集包括ILC1s、ILC2s和ILC3s。3型先天淋巴样细胞（Type 3 innate lymphoid cells, ILC3s）组成性地产生细胞因子IL-17和IL-22，在胃肠道粘膜免疫和炎症的调节中起关键作用。转录因子RORgt是ILC3s的主要调控因子，关键控制其发育和功能。然而，尽管这一基本作用，诱导、控制和维持RORgt在ILC3s中的表达的信号和分子机制尚不清楚。有趣的是，我们和其他人最近可以确定转录因子c-Maf是适应性RORgt+ 3型免疫细胞的中心调节因子。详细地说，c-Maf被证明直接结合和控制Rorc基因座。因此，c- maf缺乏导致各种RORgt+ T细胞亚群中RORgt表达下调。重要的是，我们的初步数据表明，c-Maf也在RORgt+ ILC3s中高表达。因此，根据ILCs和T细胞共享关键转录模块的概念，我们认为c-Maf代表了先天和适应性免疫区RORgt表达细胞的中心调节因子。总的来说，这个项目的目的是研究c-Maf在ILC3s的发育和功能中的作用。通过结合新的小鼠模型（例如ILC3中c-Maf的条件缺失）和分子工具（例如c-Maf结合分析），我们将剖析不同ILC3亚群中c-Maf的功能和潜在的分子电路。此外，我们的目标是确定在ILC3s中调节c-Maf表达的特定信号和机制。此外，我们的初步数据表明，在骨髓中的ILC祖细胞中存在一种独特的表达c-Maf的细胞群，这表明c-Maf也代表了早期ILC3发育的一种新的调节因子。因此，c-Maf在ILC3个体发生中的作用也将被详细研究。总之，该项目将使我们能够确定ILC3发育、稳态和功能的新调控机制。

Recently, it has become evident that innate lymphoid cells (ILCs), which represent a novel tissue-resident lymphocyte subfamily, contribute to multiple immune pathways by e.g. controlling host-microbiota interactions, potentiating adaptive immunity, and regulating tissue inflammation. Importantly, the function of ILCs also extends beyond classical immunology to metabolic homeostasis or tissue remodelling. Given this multi-facetted function, the identification of the molecular pathways governing ILC development and function is fundamental to better understand their biology as well as to develop novel strategies to manipulate these cells. In general, ILCs are divided into three subgroups based on their master transcription factor usage and cytokine‐producing capacity. These subsets include ILC1s, ILC2s and ILC3s. Type 3 innate lymphoid cells (ILC3s), which constitutively produce the cytokines IL-17 and IL-22, play key roles in the regulation of mucosal immunity and inflammation in the gastrointestinal tract. The transcription factor RORgt acts as a master regulator for ILC3s that critically controls their development and function. However, despite this fundamental role, the signals and molecular mechanisms that induce, control and maintain the expression of RORgt in ILC3s are poorly understood. Interestingly, we and others could recently identify the transcription factor c-Maf as a central regulator of adaptive RORgt+ type 3 immune cells. In detail, c-Maf was shown to directly bind and control the Rorc locus. Consequently, c-Maf-deficiency resulted in downregulation of RORgt expression in various RORgt+ T cell subsets. Importantly, our preliminary data demonstrate that c-Maf is also highly expressed by RORgt+ ILC3s. Thus, in accordance with the concept that ILCs and T cells share key transcriptional modules, we believe that c-Maf represents a central regulator of RORgt expressing cells in both the innate and adaptive immune compartment. Collectively, the aim of this project is to study the role of c-Maf for the development and function of ILC3s. By combining novel mouse models (e.g. conditional deletion of c-Maf in ILC3s) and molecular tools (e.g. c-Maf binding analysis) we will dissect the function of c-Maf and the underlying molecular circuits in different ILC3 subsets. Furthermore, we aim to identify the specific signals and mechanisms that regulate c-Maf expression in ILC3s. In addition, our preliminary data demonstrate the presence of a distinct c-Maf-expressing cell population among ILC progenitors in the bone marrow, suggesting that c-Maf also represents a novel regulator in early ILC3 development. Therefore, the role of c-Maf during ILC3 ontogeny will also be studied in detail. In summary, this project will enable us to identify novel regulatory mechanisms governing ILC3 development, homeostasis and function.