Multi-omic profiling of human antibody-secreting cells reveals diverse subsets sustain durable humoral immunity

ABSTRACT Antibody-secreting cells (ASCs) provide humoral immunity that can mediate lifelong protection against pathogens. Current classifications cannot delineate the heterogenous functionalities, tissue residencies, and lifespans of human ASC subsets, impeding clinical translation. We applied multi-omic sequencing, spatial proteomics, and functional assays to discover and characterize human bone marrow (BM) ASC subsets. We identified two peripheral subsets (ASCp) also present in blood and three BM-resident subsets (ASCr), comprising a maturation continuum associated with increased mitochondrial networking, diminished antibody secretion, differential transcription factor motif accessibility, and preferential co-localization in homotypic niches. CD19+9+ASCr and CD19-ASCr exhibited poor recovery years after BM transplantation, indicating a strong dependence on supportive niches. Childhood vaccine antigens were recognized by long-lived ASCr subsets in adults and by immature HLA-DR+ASCp, implying ASCs can differentiate without recent antigen exposure. Our results provide new insights into ASC identity, maturation, and longevity and a generalizable framework for study and manipulation of human ASCs. Competing Interest Statement A.W.G is on the science advisory board of Foundry Biosciences. D.J.G. has received research funding, has served as an adviser, and has received royalties from Juno Therapeutics, a BMS company; has served as an adviser, and received research funding from Janssen Biotech and Seattle Genetics; has served as an adviser for GlaxoSmithKline, Celgene, Ensoma, and Legend Biotech; and has received research funding from SpringWorks Therapeutics, Sano, and Cellectar Biosciences. E.W.N. is a cofounder, adviser, and shareholder of ImmunoScape.