Coordination of Innate and Adaptive Immunity in Intestinal Barrier Defense

项目总结 肠屏障防御中先天免疫与获得性免疫的协调肠屏障防御 需要先天免疫细胞和获得性免疫细胞对粘膜上皮的作用。组织驻留和 移动的先天免疫细胞和获得性免疫细胞都有助于肠道的屏障防御，但这些细胞如何 种群在病原体威胁条件下的协调还没有完全了解。白介素22 是IL-10家族的一种细胞因子，由3型免疫细胞产生，如3型固有淋巴样细胞(ILC3s) 以及作用于屏障组织上皮细胞以防止细胞外侵袭的Th17途径的细胞 病原体。IL-22如何协调肠道屏障功能仍未明确。像许多免疫的人一样 参与宿主防御的细胞因子IL-22在慢性免疫介导性疾病中上调，并且它 似乎在炎症性肠病(IBD)中起到保护作用，可能是通过抑制上皮细胞 T细胞对肠道微生物组分反应失调引起的损伤。然而，支持- IL-22的增殖作用也与结肠上皮细胞的恶性转化有关 导致结直肠癌(CRC)。我们和其他人已经证明，在由 肠道病原体，罗氏梭状芽孢杆菌，IL-22的产生有两个阶段可以区分：早期 以IL-22+天然免疫细胞为主的晚期，以IL-22+T细胞为主的晚期。 虽然先天免疫细胞和获得性免疫细胞在感染期间都会产生IL-22，但它们各自对 屏障保护是未知的，IL-22的作用机制也是未知的。在初步研究中， 使用了新的IL-22报告/条件性基因敲除(CKO)小鼠来跟踪和/或删除特定的 产生IL-22的免疫细胞亚群，我们发现产生IL-22的位置和功能 在轮状芽胞杆菌感染过程中，细胞明显不同。以ILC3s为主的先天免疫细胞主要位于 在和局限于分离的淋巴滤泡内，由IL-23激活的IL-22的释放长期作用于 在细菌定植的起始部位激活表面结肠上皮细胞。然而，值得注意的是，ILC3失败了 保护以T细胞为靶点的IL-22缺乏症小鼠被细菌侵袭的肠腺。 因此，产生IL-22的T细胞对肠道隐窝的保护是必不可少的，因为它们激活了隐窝- 衬里上皮。此外，我们还发现了结肠吸收肠细胞内新的异质性和 发现产生IL-22的T细胞以不同的方式激活这些群体，以增加脱落和产生 中性粒细胞募集趋化因子。在本提案中，我们将定义先天机制和适应性机制 免疫细胞对不同的结肠上皮细胞亚群具有不同的IL-22依赖作用， 关注IL-22+T细胞保护结肠隐窝免受细菌入侵的新功能。这些研究证明 承诺揭示肠道宿主防御和免疫细胞亚群特化的新见解 IBD和CRC的肠道炎症控制机制。

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.