Mapping human B-cell development across the lifespan reveals an HSC-independent early-life lineage as the cell-of-origin for long-lived public antibodies against self and common pathogens 3407

Abstract Description B cells generated during gestation harbor a distinct genetic program that defines the B-cell compartment at birth. We have surveyed human B-cell development across gestation in the fetal liver (n = 40) and the adult bone marrow (n = 10) using multi-omics single-cell sequencing and flow cytometry. This map has revealed both conserved processes and a fetal-exclusive B-cell program that initiates in the first trimester before the emergence of the first Hematopoietic Stem Cell (HSC). Genes controlling mouse early-life B-1 development also exclusively regulate human fetal progenitors and support their enhanced survival and altered cytokine requirements. We show that the early-life program is not solely dependent on the fetal environment. Notably, fetal but not adult CD34+ progenitors generated B cells that persisted for over one year in humanized mice and differentiated to antibody-secreting cells without exogenous stimulation. In addition, they develop B-cell receptor sequences in the host that match the donor repertoire, revealing a cell-intrinsic and deterministic mechanism to generate public antibodies. Strikingly, the early-life B-cell lineage generates highly public B-cell clones (>100 shared across individuals including a stereotyped clone that binds phosphorylcholine). Studying the developmental origin of early-life B cells that bind self, commensals, and pathogens reveals how our layered immune system has evolved to maintain homeostasis while guarding against infection. Funding Sources Supported by the Bill & Melinda Gates Foundation, Lowance Center for Human Immunology, and the National Science Foundation (NSF) Graduate Research Fellowship Program (GRFP). Topic Categories Hematopoiesis and Immune System Development (HEM)