The role of Id2 in gut innate lymphoid cells

描述（由申请人提供）：急性粘膜感染仍然是全球最重要的健康问题。ROR吗?t和il - 23/STAT3信号通路在ROR中的作用t+组-3先天淋巴样细胞（ILC3s）对IL-22的产生至关重要，而IL-22的产生是防止啮齿动物结肠炎所必需的。我们最近发现来自ILC3s的淋巴素（LT）也可以控制IL-22的产生。IL-7R信号是维持ilc3所必需的。转录因子Id2是ILC祖细胞发育所必需的，因为Id2-/-小鼠缺乏所有的ILC谱系；然而，Id2在ILC3发育后仍高表达，Id2是否调节分化ROR的功能尚不清楚。t+ ILC3s，如果是，如何执行。为了解决Id2在ILC3s的稳态和/或功能中的作用，我们产生了仅在ROR？t+ ILC3s (ROR？t-Id2-/-小鼠)，观察到它们IL-7R、IL-23R、LT和IL-22表达减少，ILC3s减少，对C.啮齿动物感染高度敏感。令人惊讶的是，协同ROR？WT小鼠的t-Id2-/-小鼠降低了ROR的死亡率和发病率。t-Id2 - / -小鼠。我们假设Id2的表达在分化的ROR？t+ ILC3s是ILC3s的稳态和功能所必需的，它可以控制肠道内的共生菌群对抗病原体的定植。在Aim 1中，我们将确定Id2如何调节各种ILC3亚群的发展。我们将测试是否需要Id2来控制IL-7R通路以及它是如何被调节的。我们还将研究Id2是否通过IL-7R信号控制ILC3s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c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是防止啮齿鼠感染所必需的。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ILC3s上的LT表达，以外部调节IL-22的产生，以对抗C.啮齿动物感染。在Aim 3中，我们将确定Id2是否通过调节和维持能够与啮齿弧菌竞争的肠道菌群来控制啮齿弧菌感染。如果是这样，我们将测试Id2依赖性反应如何调节保护性肠道菌群对抗啮齿鼠。我们将进一步确定这种选择是否由ilc3衍生的IL-22介导。最后，我们将确定Id2依赖性肠道菌群如何控制啮齿c感染。在ROR中研究Id2 ？t+ ILC3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，防止肠道粘膜感染。

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.