The role of Id2 in gut innate lymphoid cells

Id2 在肠道先天淋巴细胞中的作用

• 批准号: 8884597
• 负责人: YANG-XIN FU
• 金额: $ 33.88万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-10 至 2015-10-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8884597
• 关键词: Acute; Address; Biological Assay; Citrobacter rodentium; Colitis; Data; Development; E protein; Exhibits; Health; Homeostasis; Host Defense; Id2 protein; Immune response; Immunity; Infection; Infection prevention; Lymphoid; Lymphoid Cell; Maintenance; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Pathway interactions; Play; Production; Reagent; Regulation; Reporting; Role; STAT3 gene; Signal Transduction; Stat5 protein; Testing; Therapeutic; Tumor Necrosis Factor-Beta; combat; experience; global health; insight; interleukin-22; mortality; pathogen; progenitor; protein E; research study; response; transcription factor

DESCRIPTION (provided by applicant): Acute mucosal infections remain a foremost global health problem. ROR?t and IL23/STAT3 signaling in ROR?t+ group-3 innate lymphoid cells (ILC3s) are critical for IL-22 production required for protection against Citrobacter rodentium colitis. We recently showed that lymphotoxin (LT) from ILC3s could also control IL-22 production. IL-7R signaling is required for maintaining ILC3s. The transcription factor Id2 is required for ILC progenitor development, since Id2-/- mice lack all ILC lineages; however, Id2 is still highly expressed after ILC3 development, and it remains unclear whether or not Id2 regulates the function of differentiated ROR?t+ ILC3s and, if so, how this is executed. To address the role of Id2 in the homeostasis and/or function of ILC3s, we generated mice deficient in Id2 only in their ROR?t+ ILC3s (ROR?t-Id2-/- mice) and observed that they have reduced ILC3s with diminished IL-7R, IL-23R, LT and IL-22 expression and became highly susceptible to C. rodentium infection. Surprisingly, cohousing ROR?t-Id2-/- mice with WT mice reduced mortality and morbidity of ROR?t-Id2-/- mice. We hypothesize that Id2 expression in differentiated ROR?t+ ILC3s is required for the homeostasis and function of ILC3s, which can control commensal flora against pathogen colonization in the gut. In Aim 1, we will determine how Id2 regulates the development of various ILC3 subsets. We will test whether or not Id2 is required to control the IL-7R pathway and how this is regulated. We will also study whether or not Id2 controls the survival or proliferative capacity of ILC3s through IL-7R signaling. Finally, we will determine how interaction of Id2 and E protein controls the IL-7R/STAT5 pathway. In Aim 2, we will define how Id2 controls host defense against C. rodentium infection. We will test whether or not Id2 expression in ILC3s promotes IL-22 production, which is required for protection against C. rodentium infection. We will test whether Id2 intrinsically regulates IL-22 production through the IL-23R pathway to protect the host against an infection. We will also determine how Id2 controls LT expression on ILC3s for extrinsic regulation of IL-22 production against C. rodentium infection. In Aim 3, we will determine whether Id2 controls C. rodentium infection through regulating and maintaining a gut flora capable of competing with C. rodentium. If so, we will test how an Id2- dependent response regulates the protective gut flora against C. rodentium. We will further determine whether the selection is mediated by ILC3-derived IL-22. Finally, we will determine how an Id2- dependent gut flora controls C. rodentium infection. Studying Id2 in ROR?t+ ILC3s will provide new insights into ILC3 development and function, which contribute to the homeostasis of gut flora that protects against a mucosal infection in the gut.

描述(由申请人提供)：急性粘膜感染仍然是一个首要的全球健康问题。ROR？T+3组固有淋巴样细胞(ILC3)中的ROR？T和IL23/STAT3信号对IL-22的产生至关重要，而IL-22是预防轮状柠檬酸杆菌结肠炎所必需的。我们最近发现来自ILC3s的淋巴毒素(LT)也可以控制IL-22的产生。IL-7R信号是维持ILC3所必需的。由于Id2-/-小鼠缺乏所有ILC谱系，因此转录因子Id2是ILC前体发育所必需的；然而，在ILC3发育后，Id2仍然高度表达，目前尚不清楚Id2是否调节分化的ROR？T+ILC3的功能，如果是的话，这是如何执行的。为了探讨Id2在ILC3s动态平衡和/或功能中的作用，我们建立了仅在RoR？T+ILC3s中Id2缺陷的小鼠(ROR？T-Id2-/-小鼠)，观察到它们减少了ILC3，IL-7R、IL-23R、LT和IL-22的表达降低，并变得对牙周炎高度易感。令人惊讶的是，ROR？T-Id2-/-小鼠与WT小鼠共居降低了ROR？T-Id2-/-小鼠的死亡率和发病率。我们推测，在分化的RoR？T+ILC3s中表达Id2是维持ILC3s的动态平衡和功能所必需的，ILC3s可以控制共生菌群以对抗肠道内的病原体定植。在目标1中，我们将确定Id2如何调节各种ILC3亚集的发育。我们将测试是否需要Id2来控制IL-7R途径，以及这是如何调节的。我们还将研究Id2是否通过IL-7R信号控制ILC3的生存或增殖能力。最后，我们将确定Id2和E蛋白的相互作用如何控制IL-7R/STAT5途径。在目标2中，我们将定义Id2如何控制宿主对轮状芽胞杆菌感染的防御。我们将测试Id2在ILC3s中的表达是否促进IL-22的产生，而IL-22是预防轮状芽胞杆菌感染所必需的。我们将测试Id2是否通过IL-23R途径内在地调节IL-22的产生，以保护宿主免受感染。我们还将确定Id2如何控制ILC3上LT的表达，以外部调节IL-22的产生以对抗轮状芽胞杆菌感染。在目标3中，我们将确定Id2是否通过调节和维持能够与轮状芽胞杆菌竞争的肠道菌群来控制轮状芽胞杆菌的感染。如果是这样的话，我们将测试依赖Id2的反应如何调节保护肠道菌群对抗轮状芽胞杆菌。我们将进一步确定选择是否由ILC3衍生的IL-22介导。最后，我们将确定依赖Id2的肠道菌群如何控制轮状芽胞杆菌感染。在RoR？T+ILC3s中研究Id2将为ILC3的发育和功能提供新的见解，这有助于肠道菌群的动态平衡，从而保护肠道免受粘膜感染。