Role of interlukin 23 and innate lymphoid cells in protective immunity

描述（由申请人提供）：在本提案中，我们试图以啮齿类动物天然病原体鼠柠檬酸杆菌（Citrobacter rodentium）作为模型生物来研究临床上重要的人类肠出血性大肠杆菌和肠出血性大肠杆菌病原体的发病机制，以了解肠道病原体的免疫反应。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），并在附着细菌下方形成富含肌动蛋白的基座，这一过程导致附着和消退（a /E）病变。感染齿状螺旋体的小鼠发生结肠炎，由于细菌的清除和保护性体液和CD4 T细胞介导的免疫反应的发展，结肠炎在两到三周内消退。欧阳伟（W. Ouyang）实验室通过诱导Reg III家族的抗微生物肽，发现IL- 22对抗感染起关键作用。我们培育的IL-23缺陷和IL-23R缺陷小鼠都极易感染啮齿鼠。因此，IL-23-Th17通路对于协调针对这种肠道病原体的免疫反应至关重要。IL-23的一个重要功能是调节IL-22的表达。IL-22已被证明可以促进肠上皮细胞的伤口愈合、增殖和抗凋亡途径，并上调抗微生物肽和粘液的产生。尽管IL-22最初被描述为仅由Th17细胞产生的细胞因子，但现在认识到IL-22可以由先天细胞大量产生，这些细胞属于一个不断增长的细胞家族，称为先天淋巴细胞（innate Lymphoid cells, ILCs）。最近，在对肠道病原体的保护性免疫中发挥最主要作用的先天细胞亚群被确定为表达表面标记物Thy1+CKit+Sca1 + CD4+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NK样细胞的一个亚群

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.