Dissecting the transcriptional and epigenetic landscape of human antibody-secreting cells in blood and bone marrow long-lived plasma cells 4589

Abstract Description Long-lived plasma cells (LLPCs) sustain lifelong antibody secretion, forming the foundation of durable immune memory. However, the molecular mechanisms underpinning LLPC survival within the bone marrow (BM) remain incompletely understood. Using single-nucleus RNA-seq and ATAC-seq (10X Multiome) from matched blood and BM antibody-secreting cells (ASCs) of healthy adults, we profiled 8,059 nuclei, generating an integrated transcriptional and epigenetic map of ASCs across their developmental continuum with unparalleled resolution. In the BM LLPC cluster, Gene Set Enrichment Analysis (GSEA) validated the enrichment of the TNF/NF-κB signaling pathway and TLR cascades, emphasizing their anti-apoptotic roles. These clusters also demonstrate increased chromatin accessibility at key loci such as RELA, TLR1, TLR6, TLR10, NFKBIA, and TAB1, underscoring the central roles of TLR and TNF-α signaling pathways in activating the NF-κB pathway. Upregulated genes such as BCL2, NFKBIZ, TNFAIP3, and BIRC3 highlighted key survival mechanisms, while motif enrichment analysis revealed significant enrichment for REL and NF-κB binding motifs, supporting chromatin-level regulation of LLPC longevity. Together, these findings advance our understanding of LLPC survival and resilience and provide a framework for improving vaccine strategies and targeted immunotherapies. Topic Categories Computational and Systems Immunology (COMP)