Progenitor Cells for High Endothelium in the Immune Response

项目摘要 高内皮微静脉（HEV）是淋巴细胞进入淋巴组织的专门门户 和慢性炎症的部位沿着平坦壁的毛细血管后小静脉，它们调节 免疫细胞在生理和病理环境中的运输，包括自身免疫性疾病、炎症和 癌HEV在淋巴结引流部位的免疫挑战急剧扩大，以支持增强的 淋巴细胞募集，新的高内皮细胞（HEC）由增殖和新生产生， 毛细血管驻留祖细胞（CRP）。控制HEV扩增和分化的分子途径 从毛细血管前体还不清楚，但产生一个全面的地图集淋巴结血液 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 参与的候选路径。因此，我们在此续期申请中的基本重点是确定和 描述了免疫应答中HEV特化和生成的新机制。在这方面 我们将从机制上定义以下途径：i）调节祖细胞稳态和过渡性EC 免疫血管生成的扩张; ii）诱导独特的“高”内皮形态和 iii）控制指导过渡性EC的细胞命运决定 向淋巴细胞募集HEV（vs非HEV PCV）分化。我们将采用创新方法， 解决这些知识的根本差距，包括scRNAseq和大规模蛋白质组学EC分析，新的 泛EC和CRP特异性基因靶向小鼠，以及操纵EC亚群特异性 基因表达。淋巴细胞内皮细胞特化和稳态机制的阐明 组织，包括调节内皮细胞的机制，控制淋巴细胞归巢，将导致新的 用于控制自身免疫炎症和用于治疗性调节免疫调节的靶点和方法 用于疫苗接种和癌症免疫的细胞运输。

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.