Examining the role of transcription factor c-maf in regulatory T cell differentiation and function in tumor tolerance and immune evasion

调节性T细胞（Tregs）是胸腺源性淋巴细胞（T细胞）的一个亚群，具有免疫抑制能力。它们在小鼠和人类的整个生命过程中都是至关重要的，因为缺乏或故障会导致系统性自身免疫的自发发展。Treg的发育和功能由关键转录因子Foxp3、功能性t细胞受体（TCR）信号传导和细胞因子IL-2的存在驱动。最近，已经确定了高活性的组织常驻Tregs（称为效应Tregs）的稳态和功能依赖于额外的环境因子（细胞因子，可溶性因子）和广泛的转录因子网络（IRF4, T-bet, Rorgt， Gata3和Bcl6），类似于辅助性T细胞分化。这使得etreg能够在非炎症状态下被剥夺IL-2的非淋巴组织环境中存活。转录因子c-maf参与T细胞中效应分子的调控，其表达受细胞因子沿TCR共刺激调控。由于缺乏c-maf的胚胎致死性，大多数功能证据是间接的，目前缺乏详细的研究。值得注意的是，到目前为止还没有关于c-maf在treg中的作用的出版物。然而，初步数据和基因表达数据显示，c-maf在活化的treg中高度表达，尤其是来自非淋巴组织的treg。c-maf与eTreg功能的关键因子（IRF4, Bach2）相互作用。因此，我们假设c-maf与etreg的分化或功能有关。利用Treg特异性缺失c-maf的小鼠模型，本项目旨在仔细研究其在Treg分化和功能中的作用。潜在改变的Treg功能将在经典分析中得到解决，但也将在肿瘤免疫学的背景下进行评估。发展中的肿瘤经常利用Tregs的免疫抑制机制来逃避有效的T细胞介导的免疫反应。因此，高活性肿瘤衍生Tregs是eTregs的理想代表，代表了癌症免疫学正在进行的研究的焦点。更深入地了解它们在肿瘤发展中的功能将对开发新的治疗策略至关重要。本项目旨在揭示c-maf在treg中的作用及其在treg分化和功能中的作用。进一步提出在肿瘤免疫逃避的背景下，以c-maf的功能为重点，加深对eTregs的理解。在这个项目中产生的知识可能有助于开发新的治疗癌症的策略。

Regulatory T cells (Tregs) represent a subset of thymus derived lymphocytes (T cells) with immune suppressive capacities. They are critically important throughout the whole life in mice and humans, since deficiencies or malfunctions cause spontaneous development of systemic autoimmunity. Treg development and function is driven by the pivotal transcription factor Foxp3, functional T-cell receptor (TCR) signaling and presence of the cytokine IL-2. Recently, it has been established that homeostasis and function of highly active, tissue resident Tregs (termed effector Tregs) relies on additional environmental factors (cytokines, soluble factors) and a broad network of transcription factors (IRF4, T-bet, Rorgt, Gata3 and Bcl6) resembling helper T cell differentiation. This allows eTregs to survive in the milieu of non-lymphoid tissues, which can be deprived of IL-2 in a non-inflammatory state.  The transcription factor c-maf was proposed to be involved in regulation of effector molecules in T cells, its expression being regulated by cytokines along TCR co-stimulation. Due to embryonically lethality of c-maf deficiency, most functional evidences are indirect and detailed studies are currently lacking. Noteworthy, there are to date no publications addressing the role of c-maf in Tregs.  Yet, preliminary data and gene expression data show that c-maf is highly expressed in activated Tregs especially from non-lymphoid tissues. c-maf interacts with factors critical for eTreg function (IRF4, Bach2). Therefore, we hypothesise that c-maf is relevant for the differentiation or function of eTregs.  Utilizing mouse models with a Treg specific deletion of c-maf, this project aims to carefully examine its role in eTreg differentiation and function. Potentially altered Treg function will be addressed in classical assays but will also be assessed in the context of tumor immunology. Developing tumors frequently employ the immune suppressive mechanisms of Tregs to escape an efficient T cell mediated immune response. Hence, highly-active tumor derived Tregs are an ideal representative for eTregs and represent a focus of ongoing research in cancer-immunology. Deeper understanding of their function in tumor development will be crucial to develop new therapeutic strategies for patient care. This project aims to uncover the role of c-maf in Tregs and its role in eTreg differentiation and function. It furthermore proposes to deepen the understanding of eTregs in the context of tumor immune evasion with an emphasis on c-maf function. The knowledge generated in this project might help to develop new therapeutic strategies in cancer treatments.