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

Aging and inflammation reduce the bone marrow B cell output. 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. This imbalanced proteostasis leaves little spare energetic capacity to support population expansion and impairs the functionality of the few B cells that do emerge. Our findings indicate that developmental NFκB dynamics pace and safeguard B-lymphopoiesis, thereby identifying additional mechanistic causes of age-associated humoral immune deficiency.