Immune Checkpoints for Intestinal Innate Lymphoid Cells

肠道先天淋巴细胞的免疫检查点

• 批准号: 9894794
• 负责人: Jennifer Kaoru Bando
• 金额: $ 9万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894794
• 关键词: Adaptor Signaling Protein; Affect; American; BLR1 gene; Bacteria; Bacterial Infections; CRISPR library; Cell Communication; Cell Line; Cell Surface Receptors; Cell physiology; Cell surface; Cells; Citrobacter rodentium; Colorectal Cancer; Communication; Defect; Development; Disease; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Epithelium; Equilibrium; Exhibits; Family; Fetal Development; Gene Expression; Genes; Genetic; Genetic Screening; Goals; Health; Helper-Inducer T-Lymphocyte; Homeostasis; Homologous Protein; Human; Immune; Immunity; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-17; Intestines; Knockout Mice; Lamina Propria; Lead; Libraries; Lymphocyte; Lymphoid Cell; Lymphoid Tissue; Mediating; Mediator of activation protein; Membrane; Microdissection; Molecular; Mucous Membrane; Mucous body substance; Mus; Mutation; Pathway interactions; Peptide Hydrolases; Pharmacology; Phenotype; Physiology; Predisposition; Process; Production; Regulation; Reporter; Research; Risk; Signal Pathway; Signal Transduction; Site; Source; Surface; TNF gene; TNFSF11 gene; TRAF2 gene; TRAF6 gene; TRANCE protein; Testing; Therapeutic; Therapeutic Intervention; Tight Junctions; Tissues; Virus; Work; antimicrobial peptide; base; chemokine receptor; cytokine; enteric infection; enteric pathogen; experimental study; gastrointestinal epithelium; genome editing; genome-wide; immune checkpoint; improved; in vivo; inflammatory disease of the intestine; insight; interleukin-22; interleukin-23; intestinal barrier; intestinal epithelium; intestinal homeostasis; lymphoid organ; member; next generation sequencing; novel; postnatal development; prevent; protein expression; receptor; response; screening; single-cell RNA sequencing; small molecule inhibitor; tertiary lymphoid organ

PROJECT SUMMARY The gut epithelial cell layer and the mucus it secretes provide a barrier between host tissues and foreign luminal contents. Compromised barrier function induced by environmental triggers and/or genetic factors is associated with inflammatory bowel disease (IBD), which affects approximately 1.6 million Americans each year and increases the risk of developing colorectal cancer. Although intestinal homeostasis is crucial for human health, we do not fully understand the underlying processes that stabilize the barrier, or how to therapeutically correct deficiencies in its function. Intestinal epithelial homeostasis is controlled by cytokines secreted by innate lymphoid cells including Lymphoid Tissue inducer (LTi) cells. These cells exert broad affects on intestinal physiology and immunity, due to their production of the cytokines IL-22 and IL-17A, which directly modulate epithelial cells. The relevance of these cytokines is apparent in IL-22- and IL-17A-deficient mice, which exhibit increased susceptibility to bacterial infection. Soluble mediators that induce cytokine production by LTi have been identified, but the field lacks a molecular paradigm for LTi inhibition. My preliminary studies indicate that the cell surface receptor RANK suppresses cytokine production in LTi. How RANKL suppresses LTi, and its relevance during various disease states is unclear. I will test the hypothesis that dual expression of RANK and RANKL on neighboring LTi cells activates TRAF6 and prevents their hyper- responsiveness during homeostasis and infection. AIM1 will determine whether direct cell-cell interactions limit LTi effector cytokine production in cryptopatches. AIM2 will identify the molecular pathways that suppress LTi during intestinal inflammation. I will also use an in vivo genetic screen to establish whether RANK signaling is the predominant mechanism of LTi suppression, or whether there are additional novel inhibitory factors. These studies will reveal molecular details about a new axis of innate lymphoid cell regulation and advance our ability to target LTi and other innate lymphocytes to improve human health.

项目摘要 肠上皮细胞层及其分泌的粘液在宿主组织和外来物之间提供屏障。 管腔内容物。由环境触发因素和/或遗传因素诱导的屏障功能受损， 与炎症性肠病（IBD）有关，IBD影响大约160万美国人， 增加患结肠直肠癌的风险。虽然肠道内稳态对于 人类健康，我们不完全了解稳定屏障的基本过程，或者如何 在治疗上纠正其功能上的缺陷。肠上皮细胞稳态受细胞因子控制 由先天性淋巴细胞包括类淋巴组织诱导（LTi）细胞分泌。这些细胞发挥广泛的 影响肠道生理和免疫，由于它们产生细胞因子IL-22和IL-17 A， 直接调节上皮细胞。这些细胞因子的相关性在IL-22和IL-17 A缺陷的人中是明显的。 小鼠，其表现出对细菌感染的易感性增加。诱导细胞因子的可溶性介质 已经鉴定了通过LTi的产生，但是该领域缺乏LTi抑制的分子范例。我 初步研究表明细胞表面受体RANK抑制LTi中细胞因子的产生。如何 RANKL抑制LTi，其在各种疾病状态中的相关性尚不清楚。我会验证这个假设 相邻LTi细胞上RANK和RANKL的双重表达激活TRAF 6并阻止其过度表达， 在体内平衡和感染期间的反应。AIM 1将决定直接细胞间相互作用是否限制 隐补丁中LTi效应细胞因子的产生。AIM 2将识别抑制LTi的分子途径 在肠道炎症期间。我还将使用体内遗传筛选来确定RANK信号传导是否是 LTi抑制的主要机制，或是否存在其他新的抑制因子。这些 研究将揭示先天淋巴细胞调节的新轴的分子细节，并提高我们的能力， 靶向LTi和其他先天淋巴细胞以改善人类健康。