Multi-omic profiling of human antibody-secreting cells reveals diverse subsets sustain durable humoral immunity
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.
Authors
- Priya Ravisankar
- Damian J. Green (ORCID: https://orcid.org/0000-0003-0477-1446)
- Vaishnavi Parthasarathy
- Veronica Hernandez (ORCID: https://orcid.org/0000-0003-2568-2565)
- Katherine Henderson (ORCID: https://orcid.org/0000-0001-8682-5051)
- Thomas F. Bumol
- Susan A. Ludmann
- Mikael Sigvardsson (ORCID: https://orcid.org/0000-0001-8527-7276)
- Claire E. Gustafson (ORCID: https://orcid.org/0000-0002-1437-6709)
- Aishwarya Chander (ORCID: https://orcid.org/0000-0002-0459-7583)
- Palak C. Genge (ORCID: https://orcid.org/0000-0002-0851-6445)
- N Kaul (ORCID: https://orcid.org/0009-0001-8265-8169)
- Mark-Phillip Pebworth (ORCID: https://orcid.org/0000-0001-8224-9480)
- Sean C. Bendall (ORCID: https://orcid.org/0000-0003-1341-2453)
- Marla C. Glass (ORCID: https://orcid.org/0000-0003-3763-0842)
- Ziyuan He (ORCID: https://orcid.org/0000-0003-3556-8248)
- Ananda W. Goldrath (ORCID: https://orcid.org/0000-0002-5900-508X)
- Jocelin Malone (ORCID: https://orcid.org/0000-0003-0794-4250)
- Morgan Weiss (ORCID: https://orcid.org/0000-0002-4189-1992)
- Evan W. Newell (ORCID: https://orcid.org/0000-0002-2889-243X)
- Matheus P. Viana (ORCID: https://orcid.org/0000-0001-9288-2108)
- Upaasana Krishnan (ORCID: https://orcid.org/0000-0001-8589-7061)
- Troy R. Torgerson (ORCID: https://orcid.org/0000-0003-3489-5036)
- Suraj Mishra (ORCID: https://orcid.org/0000-0002-8922-9068)
- Peter J. Skene (ORCID: https://orcid.org/0000-0001-8965-5326)
- Julian Reading (ORCID: https://orcid.org/0000-0002-8533-3992)
- Lucas T. Graybuck (ORCID: https://orcid.org/0000-0002-8814-6818)
- Zachary Thomson (ORCID: https://orcid.org/0000-0002-3861-9998)
- David R. Glass (ORCID: https://orcid.org/0000-0001-9924-167X)
- Melinda L. Angus-Hill (ORCID: https://orcid.org/0000-0003-1648-1569)
- Elisabeth M. Dornisch (ORCID: https://orcid.org/0009-0009-6969-8690)
- Ashwin Samudre (ORCID: https://orcid.org/0000-0001-8136-7645)
- Cole Phalen (ORCID: https://orcid.org/0000-0002-0196-2805)
- Stephanie Añover-Sombke (ORCID: https://orcid.org/0000-0002-8530-8068)
- Tyanna Stuckey (ORCID: https://orcid.org/0009-0003-3262-8441)
- Mackenzie S. Kopp (ORCID: https://orcid.org/0000-0002-7436-5622)
- Peter J. Wittig (ORCID: https://orcid.org/0009-0000-9639-5518)
- Blessing Musgrove
- Nina Estep
- Sydney Kuhl (ORCID: https://orcid.org/0009-0008-9462-5314)
- Mebdh A. Dillon (ORCID: https://orcid.org/0009-0006-6960-1084)
- Xiao-jun Li (ORCID: https://orcid.org/0000-0003-0832-9479)
Institutions
- University of California San Diego (US)
- Fred Hutch Cancer Center (US)
- Allen Institute for Immunology (US)
- Sylvester Comprehensive Cancer Center (US)
- Allen Institute for Cell Science (US)
- Stanford University (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-04-17
- DOI
- https://doi.org/10.64898/2026.04.13.717827
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- American Society of Hematology
- Fred Hutchinson Cancer Research Center
- National Institutes of Health