Dynamic NFκB control during B-lymphopoiesis ensures proteostasis to enable phased proliferation and differentiation decisions

While myeloid bias among multipotent progenitors is one cause, how the developmental cascade of B-committed progenitors is affected remains less well characterized. Here, we identify dynamic modulation of NFκB as a hallmark of healthy lymphopoiesis, which is diminished in aged, B-lymphopenic mice.

Indeed, dysregulated NFκB dynamics result in severe B-lymphopenia. Model-aided analysis of in vivo progenitor populations and ex vivo experimental time courses reveal that accelerated differentiation of pro-B cells results in skipping critical proliferative phases. Single-cell transcriptomics confirmed premature cell-state transitions, characterized by inappropriate activation of NFκB target genes that cause wholesale increases in protein synthesis rates.