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Role of interlukin 23 and innate lymphoid cells in protective immunity

白介素 23 和先天淋巴细胞在保护性免疫中的作用

基本信息

批准号：
8499252
负责人：
Mohamed Oukka
金额：
$ 22.8万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8499252
关键词：
Actins Animal Model Apoptotic Bacteria CD4 Positive T Lymphocytes Cells Characteristics Chronic Citrobacter rodentium Colitis Crohn&apos s disease Data Developing Countries Development Diarrhea Disease Enteral Epithelial Cells Escherichia coli Escherichia coli EHEC Family Hemolytic-Uremic Syndrome Homeostasis Human Immune Immune response Immunity Immunocompetent Infant Infection Inflammation Inflammatory disease of the intestine Interferons Interleukin-17 Interleukins Intestinal Diseases Intestines Invaded Laboratories Lamina Propria Lead Lesion Lymphoid Cell Maintenance Mediating Meningitis Mucous body substance Mus Neonatal Pathogenesis Pathway interactions Peptides Phenotype Play Process Production Reporter Rodent Role Source Surface T-Lymphocyte Tissues Tumor Necrosis Factor-alpha Urinary tract infection Wound Healing antimicrobial cell mediated immune response cellular microvillus clinically significant commensal microbes cytokine enteric pathogen enteropathogenic Escherichia coli in vivo interleukin-22 interleukin-23 intestinal epithelium macrophage microbial pathogen pathogenic Escherichia coli pathogenic bacteria response

项目摘要

DESCRIPTION (provided by applicant): In this proposal, we seek to understand the immune response to enteric pathogens using Citrobacter rodentium the natural rodent pathogen as a model organism for the study of pathogenesis of the clinically significant human EPEC and EHEC pathogens. Like the human strains, C. rodentium attach to the intestinal epithelium, lead to loss (effacement) of microvilli, and the formation of actin-rich pedestals underneath the adherent bacteria, a process leading to attaching and effacing (A/E) lesions. Mice infected with C. rodentium develop colitis that resolves within two to three weeks due to clearance of bacteria and development of a protective humoral and CD4 T cell mediated immune response. The laboratory of W. Ouyang showed that IL- 22 was critical for protection against the infection through the induction of anti-microbial peptides of the Reg III family. IL-23 deficient and IL-23R deficient mice that we have generated are both extremely susceptible to C. rodentium. Thus, the IL-23-Th17 pathway is critical for orchestrating immune responses against this enteric pathogen. One important function of IL-23 is to regulate IL-22 expression. IL-22 has been shown to promote wound healing, proliferation, and anti-apoptotic pathways in intestinal epithelial cells and it also up-regulates anti-microbial peptide and mucus production Although IL-22 was originally described as a cytokine produced only by Th17 cells, it is now recognized that IL-22 can be produced in large quantities by innate cells that belong to a growing family of cells called Innate Lymphoid cells (ILCs). Recently the subset of innate cells hat play the most dominant role in protective immunity against enteric pathogens and that produce the most IL-22 in response to IL-23 during the course of an infection was identified as LTi-like cells that expres the surface markers Thy1+CKit+Sca1 CD4+. However in another study it was found that the innate source of IL-22 during infection was not LTi cell but a subset of NK like cells that express the marker NKP46 and the transcriptional factor Rorgt. However, identifying this subset by using markers such as SCA1 or NKp46 to identify this subset may not be reliable, as these markers can be up-regulated upon activation. Although it is clear the ILcs are an important source of IL-22, our data indicate that during Citrobacter Rodentium infection as early as day 4 four post infection a large amount of IL-22 is produced by T cells that express also IL-23R that we call Th22 cells TCR ab bearing T cells and not by ILCs. To study the interplay between ILCs and T cells during the course of an infection by an enteric pathogen we propose the following aims: Aim1: Identification of the Innate subset that mediate protection to enteric pathogen and Aim2: Role of Th22 versus ILcs cells in protective immunity. Understanding how these pathogenic bacteria induce inflammation and host response is critical to understanding how protective immune response can promote the clearance of enteric pathogens.

描述（由申请方提供）：在本提案中，我们试图了解对肠道病原体的免疫应答，使用啮齿类柠檬酸杆菌（天然啮齿类病原体）作为研究具有临床意义的人类EPEC和EHEC病原体发病机制的模式生物。与人类菌株一样，C.啮齿动物附着在肠上皮上，导致微绒毛的丢失（消失），并在附着的细菌下面形成富含肌动蛋白的细胞，这一过程导致附着和消失（A/E）病变。感染C.啮齿类动物发生结肠炎，由于细菌清除和保护性体液和CD 4 T细胞介导的免疫应答的发展，结肠炎在两到三周内消退。W. Ouyang表明，IL- 22通过诱导Reg III家族的抗微生物肽来保护免受感染至关重要。我们所产生的IL-23缺陷和IL-23 R缺陷小鼠都对C.啮齿动物。因此，IL-23-Th 17通路对于协调针对这种肠道病原体的免疫应答至关重要。IL-23的一个重要功能是调节IL-22的表达。IL-22已经显示出促进肠上皮细胞中的伤口愈合、增殖和抗凋亡途径，并且它还上调抗微生物肽和粘液的产生。虽然IL-22最初被描述为仅由Th 17细胞产生的细胞因子，现在认识到IL-22可以由属于称为先天性类淋巴细胞的生长细胞家族的先天性细胞大量产生（国际法委员会）。最近，在针对肠道病原体的保护性免疫中发挥最主要作用并且在感染过程中响应于IL-23产生最多IL-22的先天性细胞亚群被鉴定为表达表面标记Thy 1 +CKit+ Sca 1 CD 4+的LTi样细胞。然而，在另一项研究中，发现感染期间IL-22的先天来源不是LTi细胞，而是表达IL-22的NK样细胞亚群。标记物NKP 46和转录因子Rogt。然而，通过使用标记物如SCA 1或NKp 46来鉴定该子集可能不可靠，因为这些标记物在激活后可以上调。尽管ILc是IL-22的重要来源是清楚的，但我们的数据表明，在啮齿类柠檬酸杆菌感染期间，早在感染后第4天，大量的IL-22由也表达IL-23 R的T细胞产生，我们称之为Th 22细胞TCR ab携带T细胞，而不是由ILc产生。为了研究在肠道病原体感染过程中ILC和T细胞之间的相互作用，我们提出了以下目标：Aim 1：鉴定介导对肠道病原体保护的先天亚群和Aim 2：Th 22相对于ILcs细胞在保护性免疫中的作用。了解这些致病菌如何诱导炎症和宿主反应对于了解保护性免疫反应如何促进肠道病原体的清除至关重要。