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最重要的全球健康问题。 ROR?t+ 3 组先天淋巴细胞 (ILC3) 中的 ROR?t 和 IL23/STAT3 信号传导对于产生预防柠檬酸杆菌结肠炎所需的 IL-22 至关重要。我们最近表明，来自 ILC3 的淋巴毒素 (LT) 也可以控制 IL-22 的产生。 IL-7R 信号传导是维持 ILC3 所必需的。 ILC 祖细胞发育需要转录因子 Id2，因为 Id2-/- 小鼠缺乏所有 ILC 谱系；然而，Id2 在 ILC3 发育后仍然高度表达，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，它是如何执行的。为了解决 Id2 在 ILC3 稳态和/或功能中的作用，我们生成了仅在 ROR?t+ ILC3 中缺乏 Id2 的小鼠（ROR?t-Id2-/- 小鼠），并观察到它们随着 IL 的减少而减少了 ILC3。 -7R、IL-23R、LT 和 IL-22 表达，并且变得对啮齿类柠檬酸杆菌感染高度敏感。令人惊讶的是，将ROR?t-Id2-/-小鼠与WT小鼠共同饲养降低了ROR?t-Id2-/-小鼠的死亡率和发病率。我们假设分化的 ROR?t+ ILC3 中的 Id2 表达对于 ILC3 的稳态和功能是必需的，ILC3 可以控制共生菌群以防止病原体在肠道定植。在目标 1 中，我们将确定 Id2 如何调节各种 ILC3 子集的发育。我们将测试 Id2 是否需要控制 IL-7R 通路以及它是如何调节的。我们还将研究 Id2 是否通过 IL-7R 信号传导控制 ILC3 的存活或增殖能力。最后，我们将确定 Id2 和 E 蛋白的相互作用如何控制 IL-7R/STAT5 通路。在目标 2 中，我们将定义 Id2 如何控制宿主对啮齿类柠檬酸杆菌感染的防御。我们将测试 ILC3 中的 Id2 表达是否促进 IL-22 的产生，这是防止啮齿类柠檬酸杆菌感染所必需的。我们将测试 Id2 是否通过 IL-23R 途径从本质上调节 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 上的 LT 表达，从而外在调节 IL-22 的产生以抵抗啮齿类动物感染。在目标 3 中，我们将确定 Id2 是否通过调节和维持能够与啮齿类柠檬酸杆菌竞争的肠道菌群来控制啮齿类柠檬酸杆菌感染。如果是这样，我们将测试 Id2 依赖性反应如何调节针对啮齿类柠檬酸杆菌的保护性肠道菌群。我们将进一步确定选择是否是由 ILC3 衍生的 IL-22 介导的。最后，我们将确定 Id2 依赖性肠道菌群如何控制啮齿类柠檬酸杆菌感染。研究 ROR?t+ ILC3 中的 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稳态，从而防止肠道粘膜感染。