Heterogeneity and Imprinting of Long-lived Plasma Cells

长寿命浆细胞的异质性和印记

• 批准号: 508936394
• 负责人: Dr. Henrik Mei
• 金额: --
• 依托单位: Deutsches Rheuma-Forschungszentrum Berlin (DRFZ)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/508936394?language=en
• 关键词: Heterogeneity; Imprinting; Long; lived; Plasma

Different long-term half-lives of specific serum antibody and autoantibody titers are evident, and the plasma cell (PC) repertoire can accommodate new specificities while maintaining established memory. Despite emerging evidence and clinical relevance of heterogenous PC subsets, the regulation of antibody titers at the level of PC subset dynamics vs. stability in the bone marrow (BM) remains unclear. We here hypothesize that subsets of BMPC are linked to distinct antibody-independent functions, and by underlying different regulation ensure the concurrent stability and adaptation of the long-lived PC pool.PC profiling by mass cytometry established a profound phenotypical diversity of human bone marrow PC (BMPC), providing us with the necessary grounds to study differential composition and dynamics of human PC subsets. Importantly, preliminary analyses disclosed novel, CD19-CD56+ and CD19-CD45- PC subsets as parts of the normal human BMPC pool (termed non-canonical PC, ncPC). NcPC were enriched for IgG+ PC, indicating selection of PC emerging from systemic B cell activation into the pool of ncPC. In contrast to PC expressing the known CD19+CD45+CD56- phenotype, ncPC expressed mRNA encoding the transcription factors FOXP2 and TCF-1, the growth factor DKK-1, and upregulated several genes encoding members of the Wnt family, Wnt receptor and signaling molecules, suggesting a role of the Wnt network selectively in the biology of ncPC. In vitro, DKK-1 enhanced expression of PC survival factors APRIL, IL-6 and CXCL12 in human stromal cells, suggesting that Wnt pathway modulation mediates a privileged crosstalk of ncPC with their environment. In this project, we will further characterize novel non-canonical PC subsets ex vivo, and study their induction in vitro in T cell-dependent and -independent manner to address the hypothesis that ncPC fate is imprinted by tissue T helper cell specific factors at the level of B cell activation. We will analyze the interrelation of ncPC with other PC subsets, such as canonical CD19+CD45+CD56- BMPC, as a basis for selective therapeutic targeting of PC subsets. We will further elucidate the functional consequences of differential CD45 and CD56 expression by BMPC for their survival and tissue localization. The project will delineate the role of FOXP2, TCF-1, DKK-1, Wnt signaling and Wnt ligand expression in human ncPC in the context of antibody-independent functions of human PC.

特异性血清抗体和自身抗体滴度的不同长期半衰期是明显的，浆细胞（PC）库可以容纳新的特异性，同时保持已建立的记忆。尽管出现了异源PC亚群的证据和临床相关性，但在PC亚群动态水平上对抗体滴度的调节与骨髓（BM）中的稳定性仍不清楚。我们假设BMPC的亚群与不同的抗体非依赖性功能相关，并通过潜在的不同调节确保了长期存活的PC池的稳定性和适应性，通过质谱细胞术建立了人类骨髓PC（BMPC）的表型多样性，为我们研究人类PC亚群的差异组成和动力学提供了必要的基础。重要的是，初步分析揭示了新的CD 19-CD 56+和CD 19-CD 45- PC亚群作为正常人BMPC库的一部分（称为非典型PC，ncPC）。NcPC富集IgG+ PC，表明从系统性B细胞活化中出现的PC选择进入ncPC库。与表达已知CD 19 + CD 45 + CD 56-表型的PC相比，ncPC表达编码转录因子FOXP 2和TCF-1、生长因子DKK-1的mRNA，并上调编码Wnt家族成员、Wnt受体和信号分子的几个基因，表明Wnt网络选择性地在ncPC生物学中发挥作用。在体外，DKK-1增强PC存活因子APRIL、IL-6和CXCL 12在人基质细胞中的表达，表明Wnt通路调节介导ncPC与其环境的特权串扰。在这个项目中，我们将进一步表征新的非典型PC亚群离体，并研究其在体外诱导T细胞依赖性和非依赖性的方式来解决的假设，即ncPC的命运是由组织T辅助细胞特异性因子在B细胞活化的水平。我们将分析ncPC与其他PC亚群的相互关系，如典型的CD 19 + CD 45 + CD 56- BMPC，作为PC亚群选择性治疗靶向的基础。我们将进一步阐明差异CD 45和CD 56表达的BMPC的生存和组织定位的功能后果。该项目将描述FOXP 2，TCF-1，DKK-1，Wnt信号传导和Wnt配体表达在人PC的抗体非依赖性功能背景下在人ncPC中的作用。