Mechanisms of ILC3 Development and Plasticity in the Gastrointestinal Tract.

ILC3 在胃肠道中的发育和可塑性机制。

• 批准号: 9077053
• 负责人: Michelle Lauren Robinette
• 金额: $ 3.02万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9077053
• 关键词: Address; Affinity; Alpha Interleukin 2 Receptor; Antigens; Bacteria; Basic Science; Biology; Blocking Antibodies; Body Weight decreased; Bone Marrow Cytometry; Bromodeoxyuridine; Cells; Characteristics; Clinical; Colitis; Cytokine Receptors; Data; Defect; Development; Disease; Equilibrium; Exhibits; Frequencies; Gastrointestinal tract structure; Goals; Human; IL7R gene; In Vitro; Inflammatory; Inflammatory Bowel Diseases; Interferon Type II; Interferons; Interleukin-15; Interleukin-2; Interleukin-7; Label; Lamina Propria; Lead; Lymphocyte; Lymphoid Cell; Measures; Modeling; Mus; Pathogenesis; Pathway interactions; Patients; Phenotype; Physiologic pulse; Process; Production; Rag1 Mouse; Reporting; Research; Research Personnel; Role; Signal Transduction; Small Intestines; Sorting - Cell Movement; Staining method; Stains; Surface; Testing; Time; Transcript; base; cytokine; gastrointestinal; in vivo; insight; interleukin-22; microbiota; mouse model; novel therapeutics; progenitor; public health relevance; receptor; research study

 DESCRIPTION (provided by applicant): The objective of this research is to define the specific roles for IL-7, IL-15, and IL-2 in gastrointestinal ILC3 development and plasticity. Compared to other lymphocytes, the greatest frequency and diversity of ILCs exist in the GI tract. Notably, ILC3, the innate counterparts of TH17, are found during homeostatic conditions at especially high frequencies here. Sustained crosstalk between ILC3 and the microbiota suggest that ILCs may have a role in IBD development, and several investigators have demonstrated that ILC compartments are altered in Chron's disease patients and in mouse models of colitis, with a decrease of IL-22 producing ILC3 and increase of inflammatory IFN producing ILC1. The mechanisms that lead to ILC3/ILC1 balance in steady state and deregulation during colitis remain incompletely understood, but evidence suggests that these processes are regulated in part by IL-7, IL-15, and IL-2. In the current paradigm of ILC development, ILC classes are thought to diverge in their cytokine requirements, as ILC1 depend on IL-15, while ILC3 are reported to require IL-7. Our preliminary studies in IL-7 receptor deficient (IL-7Ra-/-) mice demonstrate that IL-7 signaling is not strictly required for NKp46- or NKp46+ ILC3 development in the siLP. However, these mice do have alterations in ILC compartments, exhibiting a reduced frequency and total number of NKp46+ ILC3, reduced total number of NKp46- ILC3, and increased frequency and number of ILC1 in the small intestine lamina propria. Furthermore, we find NKp46+ ILC3 are significantly reduced in IL2ra-/- mice compared to IL2ra+/- control. Based on our preliminary data, we challenge the current paradigm of ILC development and hypothesize that IL-7, IL-15, and IL-2 can provide partially redundant survival signals to ILC3, but also have non-redundant roles by modulating development, plasticity, and function. This hypothesis raises important questions that will be addressed in this proposal: 1) How does loss of IL-7 signaling result in an ILC3 defect; 2) What is the role of IL-15 and IL-2 in ILC3 development and plasticity? To determine how IL- 7 regulates ILC3, we will perform experiments in IL7Ra-/- and IL7Ra-/- x Rag1-/- mice. To determine the role of IL-15 and IL-2 in ILC3 development and plasticity, we will perform experiments in IL-2ra-/-, IL-15-/-, and IL7Ra-/- x IL-15-/- mice. The long-term goal of this proposed research is a better understanding of IBD pathogenesis.

 描述（由申请人提供）：本研究的目的是确定IL-7、IL-15和IL-2在胃肠道ILC 3发育和可塑性中的特定作用。与其他淋巴细胞相比，ILC在胃肠道中存在的频率和多样性最高。值得注意的是，ILC 3，TH 17的先天对应物，在稳态条件下以特别高的频率被发现。ILC 3和微生物群之间的持续串扰表明ILC可能在IBD发展中起作用，并且几个研究者已经证明，在克罗恩病患者和结肠炎小鼠模型中，ILC隔室被改变，产生ILC 3的IL-22减少，产生ILC 1的炎性IFN γ增加。在结肠炎期间导致ILC 3/ILC 1稳态平衡和失调的机制仍不完全清楚，但有证据表明这些过程部分受IL-7、IL-15和IL-2调节。在ILC发展的当前范例中，ILC类别被认为在它们的细胞因子需求方面是不同的，因为ILC 1依赖于IL-15，而ILC 3据报道需要IL-7。我们在IL-7受体缺陷（IL-7 Ra-/-）小鼠中的初步研究表明，IL-7信号传导对于siLP中的NKp 46-或NKp 46 + ILC 3发育不是严格需要的。然而，这些小鼠的ILC区室确实发生了改变，表现出小肠固有层中NKp 46 + ILC 3的频率和总数减少，NKp 46-ILC 3的总数减少，ILC 1的频率和数量增加。此外，我们发现与IL 2 ra +/-对照相比，NKp 46 + ILC 3在IL 2 ra-/-小鼠中显著减少。基于我们的初步数据，我们挑战了目前的ILC发展模式，并假设IL-7，IL-15和IL-2可以为ILC 3提供部分冗余的生存信号，但也可以通过调节发育，可塑性和功能发挥非冗余作用。这一假设提出了一些重要的问题，将在本提案中解决：1）IL-7信号转导的损失如何导致ILC 3缺陷; 2）IL-15和IL-2在ILC 3发育和可塑性中的作用是什么？为了确定IL- 7如何调节ILC 3，我们将在IL 7 Ra-/-和IL 7 Ra-/- x Rag 1-/-小鼠中进行实验。为了确定IL-15和IL-2在ILC 3发育和可塑性中的作用，我们将在IL-2 ra-/-、IL-15-/-和IL 7 Ra-/- x IL-15-/-小鼠中进行实验。这项研究的长期目标是更好地了解IBD的发病机制。