Abstract
Abstract Description Antibody-secreting plasma cells (PCs) play both protective and pathogenic roles across various disease contexts. The lifespan of PCs ranges from days to decades, and they exhibit diverse functionality including antibody secretion, cytokine production, and immunoregulation. Currently, we cannot identify, ascribe function to, nor manipulate distinct human PC subsets, preventing targeted therapeutic intervention and selective induction. To discover and characterize human PC subsets, we paired a systems immunology approach with a suite of functional assays investigating cellular identity and behavior. To identify cell surface markers expressed by human PCs, we quantified the expression of hundreds of surface proteins on millions of PCs from healthy human tissues. We then developed a bespoke PC-focused antibody panel and applied it to healthy human bone marrow in a tri-modal single-cell sequencing assay measuring surface protein expression, transcriptomics, and chromatin accessibility. We identified distinct PC subsets and dissected their molecular and epigenetic features. We sorted PC subsets and evaluated their morphology, antibody secretion rates, cytokine production, and longevity. Overall, our deep phenotypic and functional profiling has revealed unappreciated PC subsets and provided the highest resolution assessment of human PC identity reported to date. Our findings promise to enhance the identification, monitoring, and therapeutic manipulation of PCs in clinical settings. Funding Sources Cancer Research Institute Irvington Postdoctoral Fellowship American Society of Hematology Fellow Scholar Award Fred Hutchinson Cancer Center Translational Data Science Integrated Research Center Pilot Award Allen Institute for Immunology Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)