Heterogeneity and Imprinting of Long-lived Plasma Cells

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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.