Tuft cell regulation of Peyers patch composition and organization

簇细胞对派尔氏斑组成和组织的调节

• 批准号: 10640203
• 负责人: Michael R Howitt
• 金额: $ 23.78万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-08 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10640203
• 关键词: Active Biological Transport; Affect; Antibody Response; Antigens; Architecture; Area; B-Lymphocytes; Biological Assay; Biology; CCL20 gene; CCR6 gene; Cell Count; Cell Differentiation process; Cell Maturation; Cell physiology; Cells; Cellular biology; Characteristics; Cues; Data; Development; Enteroendocrine Cell; Epithelium; Flow Cytometry; Foundations; Gene Expression; Gene Expression Profile; Goals; Goblet Cells; Gut associated lymphoid tissue; Heterogeneity; Immune; Immune response; Immune system; Immunity; Immunoglobulin A; Immunology; In Situ; Intestines; Location; Lymphoid Tissue; M cell; Maps; Measures; Mediating; Methodology; Microanatomy; Microbe; Microscopy; Modeling; Mouse Strains; Mucous Membrane; Mucous body substance; Mus; Paneth Cells; Parasites; Pathogenesis; Peyer' s Patches; Play; Population; Process; Publishing; Qualifying; Regulation; Reporter; Resolution; Role; Sampling; Sensory; Sentinel; Shapes; Site; Small Intestines; Spatial Distribution; Swelling; T-Lymphocyte; Taste Perception; Testing; Thinness; Tissues; Tritrichomonas; Villous; Villus; Work; chemokine; enteric pathogen; eosinophil; experience; experimental study; feeding; food antigen; gastrointestinal; gut microbiota; in vivo; insight; lymphoid structures; microbial; microbiota; microorganism antigen; mouse model; mucosal vaccine; novel; oral tolerance; oral vaccine; pathogen; single-cell RNA sequencing; trafficking; transcriptome sequencing; transcriptomics; tumor-immune system interactions; vaccinology

Project Summary Peyer’s patches are gastrointestinal-associated lymphoid tissues found in the small intestine that function as critical induction sites of antigen-specific immunity in the gut. Food and microbial antigens are actively transported from the intestinal lumen and delivered to underlying immune cells in Peyer’s patches by specialized microfold (M) cells within the follicular-associated epithelium (FAE). To facilitate the acquisition of intestinal antigens, the FAE has a thin mucus layer with dramatically fewer goblet cells compared to the adjoining villous epithelium. Furthermore, the FAE is mostly devoid of other specialized epithelial subsets found in the villi, including Paneth cells and enteroendocrine cells, but whether tuft cells populate the FAE remains unknown. We and others found that villous tuft cells use their unique chemosensory capabilities to detect parasites and initiate type 2 immunity and tissue remodeling. Our preliminary data shows that the FAE contains numerous tuft cells, which can influence the immune cell populations in the Peyer’s patch. Therefore, we hypothesize that tuft cells act as microbial sentinels that shape the cellular composition and organization of Peyer’s patches. In Aim 1, we will employ a novel reporter mouse strain to examine the influence of tuft cells and symbiotic protists on M cell development and heterogeneity. In Aim 2, we identify tuft cell-mediated changes to the immune cell composition and spatial organization in Peyer’s patches. We have assembled a team with expertise in all the major areas of this proposal, including Dr. Eugene Butcher, who is an expert on immune cell trafficking in mucosal and lymphoid tissues. Together these studies will reveal an previously unrecognized role for tuft cells in Peyer’s patch biology and provide a foundation to understand how tuft cells influence antigen-specific immune responses to enteric pathogens and mucosal vaccines.

项目摘要 派尔集合淋巴结是小肠中发现的胃肠道相关淋巴组织， 作为肠道中抗原特异性免疫的关键诱导位点发挥作用。食品和微生物抗原 从肠腔主动转运到派伊尔氏病的免疫细胞 毛囊相关上皮（FAE）内的特化微褶（M）细胞形成的斑块。以促进 由于获得了肠抗原，FAE具有薄的粘液层，杯状细胞显著减少 与相邻的绒毛上皮相比。此外，FAE大多缺乏其他专门的 上皮细胞亚群中发现绒毛，包括潘氏细胞和肠内分泌细胞，但是否簇 FAE中的细胞仍然未知我们和其他人发现绒毛丛细胞利用其独特的 化学感应能力，以检测寄生虫和启动2型免疫和组织重塑。我们 初步数据显示，FAE含有大量簇细胞，这些细胞可以影响免疫细胞 派尔氏斑的种群数量因此，我们假设簇状细胞作为微生物的哨兵， 塑造派尔集合淋巴结的细胞组成和组织。在目标1中，我们将使用一个小说 报告小鼠品系，以检查簇状细胞和共生原生生物对M细胞发育的影响 和异质性。在目标2中，我们确定了簇细胞介导的免疫细胞组成的变化， 派尔集合淋巴结的空间组织我们已经组建了一个在所有主要领域都有专业知识的团队 包括尤金布彻博士，他是粘膜免疫细胞运输的专家， 和淋巴组织。这些研究将揭示一个以前未被认识的作用，簇细胞 并为理解簇状细胞如何影响抗原特异性 对肠道病原体和粘膜疫苗的免疫应答。