Cbfb2 gene dosage programs the differential lymphoid lineage developmental potential of fetal and adult hematopoietic progenitors

Abstract Innate-like lymphocyte subsets are generated predominantly during early-life windows, yet the mechanisms that restrict their development in adulthood remain unclear. Here we identify Cbfb2 gene dosage as a quantitative regulator of stage-specific lymphoid potential. We show that reduction of CBFβ2 levels unlocks fetal-like competence in adult hematopoietic progenitors, enabling robust generation of IL-17–producing γδ T (Tγδ17) cells. Although Cbfb2 haploinsufficiency minimally alters steady-state transcription, chromatin profiling of H3K4me3 revealed promoter-level changes in adult lymphoid-primed multipotent progenitors consistent with altered developmental priming. In adult bone marrow chimeras, Cbfb + /2m progenitors efficiently generated functional Vγ2 + Tγδ17 cells in lymph nodes and skin, and restoring Cbfb2 expression suppressed this capacity, establishing a dosage-dependent mechanism. Using an optimized in utero transplantation system, we further demonstrate that fetal niches amplify this latent competence and selectively favor IL-17–committed γδ T cell differentiation over conventional αβ T cell output. Notch1 haploinsufficiency enhanced Tγδ17 generation and phenocopied the effect of CBFβ2 dosage reduction, linking quantitative NOTCH1 signaling to innate-like lymphocyte developmental programming. Together, these findings reveal that fetal versus adult lymphopoiesis is governed by quantitative tuning of RUNX:CBFβ activity and uncover unexpected plasticity in adult hematopoiesis controlled by transcription factor dosage.