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

• 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
• 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

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.

项目总结