Regulation of human IL12/IL23 responsiveness by IL12RB1

摘要 结核病(TB)是由结核分枝杆菌(Mtb)引起的人类疾病。在……里面 2015年，结核病超过艾滋病毒/艾滋病，成为全球主要的死亡原因。IL12RB1基因调控人类 通过促进依赖细胞因子(IL12/IL23)的幼稚TH细胞分化为TH1和TH1来抵抗结核病 这17个效应器。Th1和TH17细胞通过激活结核杆菌感染的巨噬细胞和募集来限制结核杆菌的存活 中性粒细胞转移到感染部位。20年前，IL12RB1被转录并翻译成 IL12Rβ1，一种位于TH细胞表面的跨膜受体，与IL12/IL23结合，然后与 辅助受体(IL12Rβ2，IL23R)激活驱动Th1/Th17的细胞内信号级联 差异化。然而，我们最近证明了IL12RB1也被转录并翻译成 第二种异构体(异构体2或Iso2)，是IL12/IL23活性的分泌型增强剂。这一机制 Iso2增强IL12/IL23活性未知。在这里，我们提出了一个研究项目，该项目既将填补重要的 我们对IL12RB1的了解存在差距，并确定了Iso2增强的机制。这个项目是 由于IL12RB1调节包括结核病耐药性在内的多种免疫反应，因此意义重大 因为它将建立一个关于天然可溶性细胞因子受体如何增强细胞因子活性的范例。这 该项目也正在由一名调查员进行，该调查员在#年已证明具有独立的专业知识和生产力。 IL12RB1-TB相互作用领域，在高度支持基础免疫学的环境中 研究。最后，我们使用的方法和途径建立在我们在分子方面的专业知识之上。 生物学、免疫学和小鼠结核病模型。有两个具体目标：(目标1)确定 异构体2增强IL12/IL23信号转导的生化机制 异构体2增加结核耐药性的机制。在我们的学习结束时，我们将扩展我们的基本 在结核病背景下对IL12RB1免疫生物学的理解，以及产生的新蛋白 作为结核病辅助治疗的潜在用途。由于IL12RB1的S的影响超出了结核病，也包括 自身免疫、癌症和特应性疾病，我们确定的机制与其他人类相关 疾病。

ABSTRACT Tuberculosis (TB) is a human disease caused by the bacterial pathogen Mycobacterium tuberculosis (Mtb). In 2015, TB ranked above HIV/AIDs as a leading cause of death worldwide. The gene IL12RB1 regulates human resistance to TB by promoting cytokine (IL12/IL23)-dependent differentiation of naïve TH cells into TH1 and TH17 effectors. TH1 and TH17 cells limit Mtb survival by activating Mtb-infected macrophages and recruiting neutrophils to infected sites. It was established >20 years ago that IL12RB1 is transcribed and translated into IL12Rβ1, a transmembrane receptor on the TH cell surface that binds IL12/IL23, and then complexes with secondary receptors (IL12Rβ2, IL23R) to activate the intracellular signaling cascades that drive TH1/TH17 differentiation. However, we recently demonstrated that IL12RB1 is also transcribed and translated into a second isoform (Isoform 2, or Iso2) that is a secreted potentiator of IL12/IL23 activity. The mechanism whereby Iso2 potentiates IL12/IL23 activity is not known. Here, we propose a research project that will both fill important gaps in our knowledge of IL12RB1 and determine the mechanism of Iso2 potentiation. This project is significant since IL12RB1 regulates multiple immune responses including TB-resistance, and innovative since it will establish a paradigm for how natural soluble cytokine receptors potentiate cytokine activity. This project is also being pursued by an investigator with demonstrated independent expertise and productivity in the field of IL12RB1-TB interactions, in an environment that is highly supportive of basic immunology research. Finally, the methods and approach we use build on our demonstrated expertise in molecular biology, immunology and the mouse TB model. There are two Specific Aims: (AIM 1) Determine the biochemical mechanism that Isoform 2 enhances IL12/IL23 signaling; (AIM 2) Determine the immunological mechanism that Isoform 2 increases TB resistance. At the end of our studies, we will have extended our basic understanding of IL12RB1 immunobiology in the context of TB, as well as generated novel proteins with potential use as an adjunct TB therapy. Since IL12RB1's influence extends beyond TB to also include autoimmunity, cancer, and atopic disease, the mechanisms we identify are relevant to these other human diseases.