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: 9253402
• 负责人: Michelle Lauren Robinette
• 金额: $ 4.9万
• 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 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9253402
• 关键词: Address; Affinity; Alpha Cell; Alpha Interleukin 2 Receptor; Antigens; Bacteria; Basic Science; Biology; Blocking Antibodies; Body Weight decreased; Bone Marrow Cytometry; Bromodeoxyuridine; Cell Compartmentation; Cells; Characteristics; Clinical; Colitis; Cytokine Receptors; Data; Defect; Development; Disease; Equilibrium; Exhibits; Frequencies; Gastrointestinal tract structure; Goals; Human; IL7R gene; Impairment; In Vitro; Inflammatory; Inflammatory Bowel Diseases; Interferon Type II; Interferons; Interleukin 7 Receptor; 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; Stem cells; Surface; Testing; Time; Transcript; base; cytokine; experimental study; gastrointestinal; in vivo; insight; interleukin-22; microbiota; mouse model; novel therapeutics; progenitor; public health relevance; receptor

 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(申请人提供)：本研究的目的是明确IL-7、IL-15和IL-2在胃肠道ILC3发育和可塑性中的具体作用。与其他淋巴细胞相比，胃肠道中ILC的出现频率和多样性最高。值得注意的是，ILC3，TH17的先天对应分子，在动态平衡条件下被发现，频率特别高。ILC3和微生物区系之间的持续串扰表明ILC可能在IBD的发展中起作用，一些研究人员已经证明，在慢性结肠病患者和小鼠结肠炎模型中，ILC的间隔区发生了变化，产生IL-22的ILC3减少，炎性干扰素产生的ILc1增加。导致ILC3/ILC1稳态平衡和结肠炎时的放松调控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的调节。在目前的ILC发展范例中，ILC类被认为在其细胞因子需求上存在差异，因为ILC1依赖于IL-15，而ILC3据报道需要IL-7。我们对IL-7受体缺陷(IL-7Ra-/-)小鼠的初步研究表明，在Silp中，NKp46-或NKp46+ILC3的发育并不严格需要IL-7信号。然而，这些小鼠的ILC区段确实发生了变化，表现为NKp46+ILC3的频率和总数减少，NKp46-ILC3的总数减少，而小肠固有层中ILc1的频率和数量增加。此外，我们发现与IL2ra+/-对照相比，IL2ra-/-小鼠的NKp46+ILC3显著减少。基于我们的初步数据，我们挑战了目前ILC发展的范式，并假设IL-7、IL-15和IL-2可以为ILC3提供部分多余的生存信号，但也通过调节发育、可塑性和功能发挥非多余的作用。这一假说提出了重要的问题，将在这一建议中解决：1)IL-7信号的丢失如何导致ILC3缺陷；2)IL-15和IL-2在ILC3的发育和可塑性中扮演什么角色？为了确定IL-7如何调节ILC3，我们将在IL7Ra-/-和IL7Ra-/-x Rag1-/-小鼠身上进行实验。为了确定IL-15和IL-2在ILC3发育和可塑性中的作用，我们将在IL-2ra-/-、IL-15-/-和IL-7ra-/-x IL-15-/-小鼠身上进行实验。这项拟议研究的长期目标是更好地了解IBD的发病机制。