Cellular ancestry determines plasma cell diversity 2257317

Abstract

Abstract Introduction Plasma cells (PCs) secrete antibodies with diverse specificities and isotypes. PCs also exhibit differences in cellular states, antibody output, and longevity. While these features are often correlated with residence tissue, the processes that lead to more durable plasma cell responses remain unclear. Our hypothesis is that cellular ancestry contributes to PC diversity. Methods We chart transcriptional and clonal diversity in human bone marrow PCs (BMPCs), circulating memory B cells (MBCs), and adenoidal germinal center B cells (GCBCs) at the single-cell level to investigate human PC heterogeneity. Using a combination of genetic and pharmacological approaches with single-cell transcriptomic read-outs, we further address our hypothesis in mice. Results We identified various cellular and immune processes that determine human BMPC heterogeneity, primarily linked to NF-kB signaling, migration/adhesion, MHC-II expression, and metabolism. Surface CD19 expression, somatic hypermutation (SHM) patterns, and clonal structure suggest that BMPCs show diverse cellular ancestry - lower SHM associates to an MBC direct ancestor, while higher SHM is linked to a GCBC direct ancestor. We further characterize the clonal overlap between BMPCs, circulating MBCs, and adenoidal GCBCs, and link it to BMPC cellular states, clonotypes, and surface CD19 expression. Using a hapten immunization mouse model, we show that MBC-derived splenic PCs exhibit increased NF-kB and ELL2-associated gene signatures, reminiscent of long-lived human BMPC gene signatures. Ongoing studies address whether MBC-derived PCs preferentially migrate to the bone marrow or have a longer lifespan than GCBC-derived PCs. Conclusion These findings highlight cellular ancestry as a previously overlooked determinant of PC heterogeneity and suggest that MBC differentiation could lead to more durable PC responses. This finding could be leveraged to induce longer-lasting humoral immunity by designing vaccination strategies that elicit MBC-derived PCs. Funding Source FASI, Sanofi, NIH Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)