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
Year: 2025
Type: article
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)
Source: The Journal of Immunology
Authors: Alexandra F. Nazzari, Junkai Yang, Krishna Kothari, Astrid Kosters, Eliver Ghosn
Institution: Emory University
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4416449042
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