The role of miR-142 in regulatory T cell Development and function

项目摘要 调节性T(Treg)细胞对维持免疫自身耐受和抑制过度反应至关重要 对感染的免疫反应。Treg细胞活性异常与自身免疫性疾病和 针对肿瘤的非生产性免疫反应。对分子机制认识不足 支配Treg细胞生物学的关键障碍之一是阻碍基于Treg细胞的有效研究的发展 治疗自身免疫和癌症的药物。MicroRNAs(MiRNAs)对基因表达的转录后调控 最近成为Treg细胞分化和功能所必需的遗传因素。因此，目标是 为了更好地理解单个miRNA是如何控制Treg细胞的中心方面的 生物学。缩小这一知识差距可能会使我们能够开发新的、有针对性的免疫疗法来治疗 特雷格细胞介导的疾病。这项建议的重点是阐明miR-142在Treg细胞中的功能。我们的 利用基因敲除小鼠模型的结果表明，miR-142是Treg细胞不可或缺的调节因子。 介导性免疫抑制。我们发现miR-142在Treg细胞中有两个不同的作用：它促进胸腺Treg 细胞分化和正向调节成熟Treg细胞的动态平衡和抑制活性。此外，我们 成熟miR-142缺陷Treg细胞功能受损与过量产生IFNG的机械联系 和信号转导，并确定了几个IFNG相关基因作为miR-142的直接分子靶点。因此，我们的 总体假设是miR-142在胸腺Treg细胞发育中起关键作用，并控制Treg细胞 丰度和功能活性。此外，我们假设miR-142调节成熟Treg细胞的动态平衡。 以及通过减弱IFNG的产生和对IFNG的反应性而发挥抑制作用。我们将测试我们的中央 有三个具体目标的假设。在目标1中，我们将研究miR-142在胸腺Treg细胞中的作用。 发展，并确定其行动模式。在目标2中，我们将确定可诱导miR-142耗尽的影响。 抗肿瘤免疫反应背景下Treg细胞的动态平衡和抑制功能。最后，在AIM中 3、明确miR-142介导的Treg细胞活性调控的分子机制。为此，我们将 确定异常的IFNG信号如何影响免疫抑制活性和动态平衡 MIR-142缺陷的Treg细胞。这项拟议的研究具有重要意义，因为它有望推动我们的 了解miRNA介导的Treg细胞功能和免疫调控机制 宽容。此外，本研究可能为开发基于miR-142的新型分子筛奠定基础 在癌症免疫治疗和自身免疫性疾病环境中调节Treg细胞活性的治疗策略。

Project Summary Regulatory T (Treg) cells are vital for maintaining immunological self-tolerance and restraining overreactive immune responses against infection. Aberrant Treg cell activity is associated with autoimmune diseases and unproductive immune responses against tumors. An insufficient understanding of the molecular mechanisms that govern Treg cell biology is one of the critical barriers hampering development of effective Treg cell-based therapies for autoimmunity and cancer. Post-transcriptional control of gene expression by microRNAs (miRNAs) has recently emerged as an essential genetic element for Treg cell differentiation and function. Thus, the objective of this proposal is to gain better understanding of how individual miRNAs control central aspects of Treg cell biology. Closing of this knowledge gap may allow us to develop novel, targeted immunotherapies for treatment of Treg cell-mediated diseases. The focus of this proposal is to elucidate the function of miR-142 in Treg cells. Our results using genetic knockout mouse models indicate that miR-142 is an indispensable regulator of Treg cell- mediated immunosuppression. We uncovered two distinct roles for miR-142 in Treg cells: it promotes thymic Treg cell differentiation and positively regulates mature Treg cell homeostasis and suppressive activity. Moreover, we mechanistically linked the impaired function of mature miR-142-deficient Treg cells with excessive IFNg production and signaling, and identified several IFNg-associated genes as direct molecular targets of miR-142. Thus, our overall hypothesis is that miR-142 plays a crucial role in thymic Treg cell development and controls Treg cell abundance and functional activity. Furthermore, we posit that miR-142 regulates mature Treg cell homeostasis and suppressive function by attenuating production of and responsiveness to IFNg. We will test our central hypothesis with three specific aims. In Aim 1, we will investigate the role of miR-142 in thymic Treg cell development and define its mode of action. In Aim 2, we will determine the impact of inducible miR-142 depletion on Treg cell homeostasis and suppressive function in the context of antitumor immune response. Finally, in Aim 3, we will identify the molecular mechanism of miR-142-mediated control of Treg cell activity. To that end, we will determine how dysregulated IFNg signaling impacts the immunosuppressive activity and homeostasis of miR-142-deficient Treg cells. The proposed research is significant because it is expected to advance our understanding of miRNA-mediated mechanisms underlying the control of Treg cell function and immune tolerance. Additionally, this study may potentially lay a foundation for developing a novel miR-142-based therapeutic strategy for modulating Treg cell activity in cancer immunotherapy and autoimmune disease settings.