Coordination of Innate and Adaptive Immunity in Intestinal Barrier Defense

肠道屏障防御中先天性免疫和适应性免疫的协调

基本信息

批准号：
10580812
负责人：
Casey T Weaver
金额：
$ 56.8万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10580812
关键词：
Anti-Bacterial Agents Antigen Presentation Bacteria Binding CD4 Positive T Lymphocytes Cell Communication Cell Line Cells Chronic Citrobacter rodentium Colon Colorectal Cancer Complex Disease Distal Enterocytes Epithelial Cells Epithelium Escherichia coli Escherichia coli EHEC Family Genes Geography Gram-Negative Bacteria Growth Heterogeneity Host Defense IL10RB gene Immune Impairment Infection Infectious colitis Inflammatory Bowel Diseases Interleukin-10 Intestines Invaded Knockout Mice Lamina Propria Location Lymphoid Cell Lymphoid Follicle Malignant - descriptor Mediating Modeling Mucous Membrane Mus Natural Immunity Natural regeneration Neutrophil Infiltration Pathogenicity Pathway interactions Phagocytes Phase Play Population Positioning Attribute Production Reporter Reporting Role STAT3 gene Signal Transduction Site Source Surface T cell response T-Lymphocyte Testing Tissues adaptive immunity antimicrobial antimicrobial peptide base cell type chemokine colonic crypt conditional knockout cytokine defined contribution enteric pathogen enteropathogenic Escherichia coli epithelial stem cell extracellular gut inflammation gut microbiome human disease insight interleukin-22 interleukin-23 intestinal barrier intestinal crypt intestinal epithelium lymphoid structures neutrophil novel pathogen prevent protective effect recruit repaired response restraint senescence

项目摘要

PROJECT SUMMARY Coordination of Innate and Adaptive Immunity in Intestinal Barrier Defense. Intestinal barrier defense requires the actions of both innate and adaptive immune cells on the mucosal epithelium. Tissue-resident and mobile innate and adaptive immune cells each contribute to barrier defense in the intestines, but how these cell populations are coordinated under conditions of pathogen threat are not fully understood. Interleukin-22 (IL-22) is a cytokine of the IL-10 family produced by type 3 immune cells, such as group 3 innate lymphoid cells (ILC3s) and cells of the Th17 pathway that acts on epithelial cells of barrier tissues to prevent invasion of extracellular pathogens. How IL-22 acts to coordinate intestinal barrier function remains undefined. Like many immune cytokines that participate in host defense, IL-22 is upregulated in chronic immune-mediated diseases, and it appears to play a protective role in inflammatory bowel disease (IBD), presumably by restraining epithelial damage caused by dysregulated T cell responses to constituents of the intestinal microbiome. However, pro- proliferative actions of IL-22 have also been implicated in malignant transformation of colonic epithelial cells that leads to colorectal cancer (CRC). We and others have shown that during infectious colitis modeled by the enteropathogen, C. rodentium, there are two phases of IL-22 production that can be distinguished: an early phase dominated by IL-22+ innate immune cells, which is followed by a late phase dominated by IL-22+ T cells. While both innate and adaptive immune cells produce IL-22 during infection, the respective contributions to barrier protection are unknown, as are details of the mechanisms by which IL-22 acts. In preliminary studies that have employed novel IL-22 reporter/conditional knockout (cKO) mice with which to track and/or delete specific subsets of IL-22-producing immune cells, we have found that the locations and functions of IL-22–producing cells are distinct during C. rodentium infection. Innate immune cells, dominated by ILC3s, are primarily located in and restricted to isolated lymphoid follicles, and their release of IL-22 activated by IL-23 acts long-range to activate surface colonic epithelial cells at initial sites of bacterial colonization. Remarkably, however, ILC3s fail to protect the intestinal crypts, which are invaded by bacteria in mice with IL-22 deficiency targeted to T cells. Thus, IL-22–producing T cells are indispensable for protection of the intestinal crypts via their activation of crypt- lining epithelium. Moreover, we have discovered new heterogeneity within colonic absorptive enterocytes and find that IL-22-producing T cells differentially activate these populations for increased shedding and production of neutrophil-recruiting chemokines. In this proposal we will define mechanisms by which innate and adaptive immune cells are specialized for distinct IL-22–dependent actions on different subsets of colonic epithelial cells, focusing on novel functions of IL-22+ T cells to protect colonic crypts from bacterial invasion. These studies hold promise to reveal new insights into specialization of immune cell subsets in intestinal host defense and mechanisms that control intestinal inflammation in IBD and CRC.

项目概要肠道屏障防御中先天性和适应性免疫的协调。需要先天性和适应性免疫细胞对粘膜上皮细胞的作用。移动的先天性免疫细胞和适应性免疫细胞都有助于肠道的屏障防御，但是这些细胞如何在尚未完全了解白介素 22 (IL-22) 病原体威胁的情况下，种群之间的协调。是 IL-10 家族的细胞因子，由 3 型免疫细胞（例如第 3 组先天淋巴细胞 (ILC3)）产生 Th17途径的细胞作用于屏障组织的上皮细胞，防止细胞外的侵袭与许多免疫系统一样，IL-22 如何协调肠道屏障功能仍不清楚。参与宿主防御的细胞因子，IL-22 在慢性免疫介导的疾病中表达上调，并且似乎在炎症性肠病 (IBD) 中发挥保护作用，可能是通过抑制上皮细胞由 T 细胞对肠道微生物组成分的损伤反应失调引起。 IL-22 的增殖作用也与结肠上皮细胞的恶性转化有关，我们和其他人已经证明，在以传染性结肠炎为模型的过程中，会导致结直肠癌（CRC）。肠道病原体（啮齿类梭菌）IL-22 的产生可分为两个阶段：早期阶段以 IL-22+ 先天免疫细胞为主的阶段，随后是以 IL-22+ T 细胞为主的晚期阶段。虽然先天性免疫细胞和适应性免疫细胞在感染过程中都会产生 IL-22，但各自的贡献屏障保护作用尚不清楚，IL-22 作用机制的细节也尚不清楚。使用新型 IL-22 报告基因/条件敲除 (cKO) 小鼠来追踪和/或删除特定的在产生 IL-22 的免疫细胞亚群中，我们发现产生 IL-22 的免疫细胞的位置和功能啮齿类动物 C. rodentium 感染期间，细胞是不同的，主要定位于以 ILC3 为主的先天免疫细胞。位于并仅限于孤立的淋巴滤泡，并且它们释放的 IL-22 被 IL-23 激活，从而发挥长程作用然而，值得注意的是，ILC3 却失败了。保护肠隐窝，这些隐窝会受到针对 T 细胞的 IL-22 缺陷小鼠的细菌入侵。因此，产生 IL-22 的 T 细胞对于通过激活隐窝来保护肠隐窝是必不可少的。此外，我们还发现了结肠吸收性肠细胞和内膜上皮的新异质性。发现产生 IL-22 的 T 细胞差异性地激活这些细胞群，以增加脱落和产量在本提案中，我们将定义先天性和适应性的机制。免疫细胞专门针对不同的结肠上皮细胞亚群发挥独特的 IL-22 依赖性作用，这些研究重点关注 IL-22+ T 细胞保护结肠隐窝免受细菌侵袭的新功能。有望揭示免疫细胞亚群在肠道宿主防御中的专业化的新见解控制 IBD 和 CRC 肠道炎症的机制。