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 Peyer‘s斑块是在小肠中发现的胃肠道相关淋巴组织 在肠道中发挥抗原特异性免疫的关键诱导部位的作用。食物和微生物抗原 主动地从肠腔转运到Peyer‘s的潜在免疫细胞 滤泡相关上皮(FAE)内特殊的微折叠(M)细胞形成的补丁。为了方便 在获得肠道抗原的过程中，FAE有一层薄的粘液层，杯状细胞显著减少 与邻近的绒毛上皮相比。此外，FAE几乎没有其他专门的 在绒毛中发现的上皮亚群，包括Paneth细胞和肠内分泌细胞，但是否丛生 FAE中填充的细胞仍不清楚。我们和其他人发现绒毛绒毛细胞利用其独特的 化学传感能力，检测寄生虫，启动2型免疫和组织重塑。我们的 初步数据显示，FAE含有大量的簇状细胞，可以影响免疫细胞 佩耶尔河流域的种群。因此，我们假设丛生细胞作为微生物的哨兵 塑造Peyer‘s斑块的细胞组成和组织。在目标1中，我们将使用一部小说 小鼠品系检测丛生细胞和共生原生原生生物对M细胞发育的影响 和异质性。在目标2中，我们确定了簇状细胞介导的免疫细胞成分的变化和 佩尔氏斑块的空间组织。我们组建了一支在所有主要领域都有专业知识的团队 这项提议的支持者包括尤金·布彻博士，他是粘膜免疫细胞运输方面的专家 和淋巴组织。总之，这些研究将揭示绒毛细胞以前未被认识到的作用 并为理解簇状细胞如何影响抗原特异性提供了基础 对肠道病原体和粘膜疫苗的免疫反应。