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一个首要的全球健康问题。吼？t和IL 23/STAT 3信号转导在ROR？t+组-3先天淋巴样细胞（ILC 3）对于IL-22的产生是至关重要的，所述IL-22的产生是防止啮齿类柠檬酸杆菌结肠炎所需的。我们最近发现，ILC 3的光毒素（LT）也可以控制IL-22的产生。IL-7 R信号传导是维持ILC 3所必需的。转录因子Id 2是ILC祖细胞发育所必需的，因为Id 2-/-小鼠缺乏所有ILC谱系;然而，Id 2在ILC 3发育后仍高度表达，目前尚不清楚Id 2是否调节分化的ROR的功能？t+ ILC 3s，如果是，如何执行。为了解决Id 2在ILC 3的稳态和/或功能中的作用，我们只在其ROR中产生Id 2缺陷的小鼠。t+ ILC3s（ROR？t-Id 2-/-小鼠），并观察到它们具有降低的ILC 3，同时降低的IL-7 R、IL-23 R、LT和IL-22表达，并变得对C.啮齿类感染令人惊讶的是，共同居住的ROR？t-Id 2-/-小鼠与WT小鼠降低死亡率和发病率的ROR？t-Id 2-/-小鼠。我们推测，Id 2表达在分化ROR？t+ ILC 3 s对于ILC 3 s的稳态和功能是必需的，ILC 3 s可以控制肠道植物群对抗肠道中的病原体定殖。在目标1中，我们将确定Id 2如何调节各种ILC 3亚群的发育。我们将测试是否需要Id 2来控制IL-7 R通路以及如何调节。我们还将研究Id 2是否通过IL-7 R信号传导控制ILC 3的存活或增殖能力。最后，我们将确定Id 2和E蛋白的相互作用如何控制IL-7 R/STAT 5通路。在目标2中，我们将定义Id 2如何控制主机对C的防御。啮齿类感染我们将测试ILC 3中Id 2的表达是否促进IL-22的产生，这是针对C.啮齿类感染我们将测试Id 2是否通过IL-23 R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Id 2如何控制ILC 3s上的LT表达，从而外源性调节IL-22的产生以对抗C。啮齿类感染在目标3中，我们将确定Id 2是否控制C。通过调节和维持肠道植物群与C.啮齿动物。如果是这样，我们将测试Id 2依赖性反应如何调节保护性肠道植物群对抗C。啮齿动物。我们将进一步确定选择是否由ILC 3衍生的IL-22介导。最后，我们将确定Id 2依赖的肠道植物群如何控制C。啮齿类感染在ROR学习Id 2？t+ ILC 3将为ILC 3的发育和功能提供新的见解，这有助于肠道植物群的稳态，从而保护肠道免受粘膜感染。

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.