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Non-redundant functions of type 3 innate lymphoid cells in mucosal immunity

3型先天淋巴细胞在粘膜免疫中的非冗余功能

基本信息

批准号：
10374839
负责人：
Ivaylo Ivanov Ivanov
金额：
$ 48.3万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10374839
关键词：
Ablation Address Adult Animals Architecture B-Lymphocytes Cell Differentiation process Cell physiology Cells Cellular Immunity Citrobacter Citrobacter rodentium Cytoprotection Data Defect Development Genetic Genetic Models Gut Mucosa Helper-Inducer T-Lymphocyte Homeostasis Host Defense Immune Immunity Immunology Infection Inflammatory Interleukin-17 Intestines Knockout Mice Knowledge Lamina Propria Lead Lymphocyte Lymphoid Cell Mediating Metabolism Modeling Molecular Mucosal Immunity Mucous Membrane Mus Pathologic Pathway interactions Peyer&apos s Patches Physiology Play Production Publishing Reporting Role Shapes Source Surface T cell differentiation T cell response T-Cell Depletion T-Cell Development T-Lymphocyte Testing Time adaptive immunity cell type commensal bacteria commensal microbes cytokine enteric pathogen gut inflammation gut microbiota host microbiota immune function improved interleukin-22 lymph nodes microbiota mortality mouse model mucosal microbiota novel preservation prevent response transcription factor

项目摘要

Type 3 innate lymphoid cells (ILC3) perform multiple functions in host physiology. However, most of these functions have been elucidated in the context of T cell depletion. There is an extensive overlap of regulatory and functional networks between ILC3 and Th17 cells and how these two cell types contribute to immunity is unclear. Identification of non-redundant functions of ILC3 has been impeded by the lack of ILC3 depletion models that preserve normal T cell development and differentiation. To address this gap in knowledge, we created the first model in which ILC3 development is prevented, but B and T cell development and T cell differentiation is normal. Using this model we demonstrate a non-redundant function of ILC3 in mucosal protection against an intestinal pathogen. We will examine the specific mechanism of this protection, as well as identify novel T cell-independent functions of ILC3. Moreover, we will uncouple the role of LTi in lymph node and Peyer’s patch development from the role of adult lamina propria ILC3. We will also investigate the role of ILC3 in regulating homeostasis with the intestinal microbiota. Overall, our studies will elucidate the cellular and molecular mechanisms controlling non-redundant ILC3 functions in both maintaining a healthy gut and regulating infectious intestinal inflammation. We expect the results to lead to the development of more specific strategies for targeting ILC3 and Th17 cells to improve intestinal immune dysbalance or prevent pathologic intestinal inflammation.

3 型先天淋巴细胞 (ILC3) 在宿主生理学中发挥多种功能。然而，这些大多数 T 细胞耗竭的背景下已阐明其功能。监管存在广泛重叠 ILC3 和 Th17 细胞之间的功能网络以及这两种细胞类型如何促进免疫尚不清楚。由于 ILC3 缺乏，ILC3 非冗余功能的鉴定受到阻碍保留正常 T 细胞发育和分化的模型。为了解决这一知识差距，我们创建了第一个模型，其中 ILC3 发育被阻止，但 B 细胞和 T 细胞发育以及 T 细胞分化是正常的。使用该模型，我们证明了 ILC3 在粘膜中的非冗余功能预防肠道病原体。我们将研究这种保护的具体机制，如以及鉴定 ILC3 的新的独立于 T 细胞的功能。此外，我们将解开 LTi 的角色淋巴结和派尔氏集结的发育来自成人固有层 ILC3 的作用。我们还将研究 ILC3 在调节肠道菌群稳态中的作用。总的来说，我们的研究将阐明控制非冗余 ILC3 功能的细胞和分子机制维持健康的肠道并调节感染性肠道炎症。我们预计结果将领先开发针对 ILC3 和 Th17 细胞的更具体策略，以改善肠道免疫失调或预防病理性肠道炎症。