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

最近，已经变得明显的是，代表新的组织驻留淋巴细胞亚家族的先天性淋巴样细胞（ILC）通过例如控制宿主-微生物群相互作用、增强适应性免疫和调节组织炎症而有助于多种免疫途径。重要的是，ILC的功能也超出了经典的免疫学，扩展到代谢稳态或组织重塑。鉴于这种多方面的功能，确定控制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操纵这些细胞的新策略至关重要。通常，ILC根据其主转录因子使用和细胞因子产生能力分为三个亚组。这些子集包括ILC 1、ILC 2和ILC 3。3型先天性淋巴样细胞（ILC 3），组成性产生细胞因子IL-17和IL-22，在胃肠道粘膜免疫和炎症的调节中发挥关键作用。转录因子RORgt作为ILC 3的主要调节因子，其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ILC 3中RORgt表达的信号和分子机制知之甚少。有趣的是，我们和其他人最近可以确定转录因子c-Maf作为适应性RORgt+3型免疫细胞的中心调节因子。详细地说，c-Maf显示直接结合和控制Rorc基因座。因此，c-Maf缺陷导致各种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，RORgt+ ILC 3也高度表达c-Maf。因此，根据ILC和T细胞共享关键转录模块的概念，我们认为c-Maf代表先天性和适应性免疫区室中表达RORgt的细胞的中心调节因子。总的来说，本项目的目的是研究c-Maf对ILC 3的发育和功能的作用。通过结合新的小鼠模型（例如ILC 3中c-Maf的条件性缺失）和分子工具（例如c-Maf结合分析），我们将剖析c-Maf的功能和不同ILC 3亚群中的潜在分子电路。此外，我们的目标是确定特定的信号和机制，调节c-Maf表达ILC 3。此外，我们的初步数据表明，在骨髓中的ILC祖细胞中存在不同的c-Maf表达细胞群，这表明c-Maf也代表了早期ILC 3发育中的新调节因子。因此，c-Maf在ILC 3个体发育过程中的作用也将被详细研究。总之，该项目将使我们能够确定新的调控机制ILC 3的发展，稳态和功能。

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.