Progenitor Cells for High Endothelium in the Immune Response

项目总结 摘要：高内皮微静脉(HEV)是淋巴细胞进入淋巴组织的特殊通道。 以及血液中的慢性炎症部位。它们与扁平的毛细血管后小静脉一起调节 生理和病理环境中的免疫细胞运输，包括自身免疫性疾病、炎症和 癌症。HEV在淋巴引流部位的免疫挑战急剧扩大，以支持增强 淋巴细胞募集，由于增殖和新生而产生新的高内皮细胞(HEC) 毛细血管常驻祖细胞(CRP)。控制HEV扩增和分化的分子途径 来自毛细血管的前体尚不清楚；但生成一份全面的淋巴结血图谱 内皮细胞亚群、分子表型和对免疫挑战的反应现在使我们能够识别 涉及的候选路径。因此，我们在此次续签申请中的基本重点是识别和 描述免疫应答中HEV特化和生成的新机制。在此背景下 我们将从机制上定义如下途径：1)调节祖细胞动态平衡和过渡性EC 免疫血管生成的扩张；ii)诱导血管内皮细胞独特的高形态和代谢 HEV，规范“HEV”和功能；以及III)控制指导过渡EC的细胞命运决定 向淋巴细胞募集型HEV(与非HEV PCV)分化。我们将创新方式应用于 解决包括scRNAseq和大量蛋白质组EC图谱在内的知识中的这些根本差距，新颖 PAN-EC和CRP-特异性基因靶向小鼠，以及操纵EC-亚集特异性的纳米颗粒方法 基因表达。淋巴组织内皮细胞特化和动态平衡机制的阐明 组织，包括调控内皮细胞控制淋巴细胞归巢的机制，将导致新的 自身免疫性炎症控制和免疫治疗调节的靶点和途径 用于疫苗接种和癌症免疫的细胞流量。

PROJECT SUMMARY SUMMARY: High endothelial venules (HEV) are specialized portals for lymphocyte entry into lymphoid tissues and sites of chronic inflammation from the blood. Along with flat walled postcapillary venules, they regulate immune cell trafficking in physiologic and pathologic settings including autoimmune diseases, inflammation and cancer. HEV in lymph nodes draining sites of immune challenge expand dramatically to support enhanced lymphocyte recruitment, with new high endothelial cells (HEC) arising by proliferation and by neogenesis from capillary resident progenitors (CRP). The molecular pathways that control HEV expansion and differentiation from capillary precursors are as yet unclear; but generation of a comprehensive atlas of lymph node blood endothelial cell subsets, molecular phenotypes and responses to immune challenge now allows us to identify candidate pathways involved. Our fundamental focus in this renewal application is therefore to identify and characterize novel mechanisms of HEV specialization and generation in the immune response. In this context we will mechanistically define pathways that i) regulate progenitor cell homeostasis and transitional EC expansion in immune angiogenesis; ii) induce the unique "high" endothelial morphology and metabolism of HEV, regulating "HEVness" and function; and iii) control the cell-fate decision that directs transitional EC towards lymphocyte-recruiting HEV (vs non-HEV PCV) differentiation. We will apply innovative approaches to address these fundamental gaps in knowledge including scRNAseq and mass proteomic EC profiling, novel pan-EC and CRP-specific gene-targeted mice, and nanoparticle methods to manipulate EC-subset specific gene expression. Elucidation of the mechanisms of endothelial cell specialization and homeostasis in lymphoid tissues, including mechanisms regulating endothelial cells that control lymphocyte homing, will lead to novel targets and approaches for the control of autoimmune inflammation and for therapeutic regulation of immune cell traffic for vaccination and cancer immunity.