Elucidating the nature of long-lived plasma cell precursors

Abstract

Abstract Plasma cells (PCs) are terminally differentiated B cells that secrete protective antibodies and serve as a source of long-term humoral memory. PC precursors appear to be generated late in the germinal center B cell response in the spleen and migrate to the bone marrow (BM) to differentiate into PCs. However, the developmental and molecular mechanisms that control the generation, migration and differentiation of precursors of long-lived PCs (LLPCs) remain to be elucidated. In order to identify and characterize the precursors of LLPCs we established a novel adoptive transfer system. C57Bl/6J mice were immunized with NP-KLH along with LPS and alum. Post-immunization, splenic CD138+ cells were isolated on days 21, 28, 35 and 42 and then adoptively transferred into the B cell deficient μMT mouse strain. Sustained NP-specific IgG1 responses were observed in the μMT recipients, with a peak following adoptive transfer of day 35, CD138+ cells. The adoptively transferred cells were demonstrated to contain LLPC precursors as they generated NP-specific IgG1+ antibody secreting cells (ASCs) in the BM that were sustained for over 2 months following transfer. These results directly demonstrate that precursors of LLPCs arise between days 28 to 42 post-immunization. Genomic analyses of LLPC precursors using scRNA-seq and Ig profiling is being used to uncover molecular mechanisms that regulate their generation and differentiation.