Dysregulated NF-κB dynamics impair proteostasis and drive premature differentiation in aging B cell development.

Aging and inflammation reduce bone marrow B cell output. While myeloid bias among multi-potent progenitors is one cause, how the developmental cascade of B-committed progenitors is affected remains less well characterized. Here, we identify dynamic modulation of the inflammation response factor NF-κB as a hallmark of healthy lymphopoiesis, but it is diminished in aged B-lymphopenic mice. Indeed, genetic dysregulation of NF-κB dynamics results in severe B-lymphopenia. Model-aided analysis of in vivo progenitor populations and ex vivo experimental time courses reveals 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 NF-κB target genes that cause wholesale increases in protein synthesis rates. This imbalanced proteostasis leaves little spare energetic capacity to support population expansion, leading to premature differentiation. Our findings indicate that developmental NF-κB dynamics safeguard B lymphopoiesis, thereby identifying a mechanistic cause of age-associated humoral immune deficiency.