NFκB RelA dynamic control in early B lymphopoiesis and aging
Aging and inflammation have been shown to reduce the supply of functional B-cells; the prevailing explanation is that hematopoietic differentiation decisions are skewed towards the myeloid lineage. Here, we have addressed how inflammaging may affect B-lymphopoiesis itself. Using a new NFκB reporter mouse, we uncovered dramatic dynamics in RelA control during early B lymphopoiesis in young but not in all aged mice. When genetically perturbing NFκB RelA dynamics with specific IκB mutants, we found severe, cell-intrinsic defects in B lymphopoiesis, that could not be attributed to a differentiation block or reduced cell survival. Careful quantification of B-lymphoid progenitors allowed us to fit a mathematical model of the differentiation pathway, which led to the seemingly paradoxical prediction – confirmed ex vivo – that mutant B-cell progenitors ‘rush through’ the differentiation pathway. Further analysis revealed the differentiation hypermorph leads to diminished mature cell populations given that differentiation pauses are essential for population expansion. Transcriptomic profiling at single-cell resolution revealed RelA dynamic dysregulation resulted in an accelerated progression of transcriptomic cell states that are not in sync with the classically defined progenitors and – importantly – overridden preBCR checkpoint. As this is a major quality control step to ensure proper immunoglobulin heavy chain recombination, the mutant triggers premature κ-light chain recombination, resulting in B-cells with nonfunctional immunoglobulin. Our findings establish a new paradigm for how aging and inflammation impact humoral immunity via dysregulation of RelA dynamics: accelerated differentiation diminishes the size and the quality of the B-cell pool available for adaptive immune responses.