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 CBF{beta}2 levels unlocks fetal-like competence in adult hematopoietic progenitors, enabling robust generation of IL-17-producing {gamma}{delta} T (T{gamma}{delta}17) 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 V{gamma}2+ T{gamma}{delta}17 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 {gamma}{delta} T cell differentiation over conventional {beta} T cell output. Notch1 haploinsufficiency enhanced T{gamma}{delta}17 generation and phenocopied the effect of CBF{beta}2 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:CBF{beta} activity and uncover unexpected plasticity in adult hematopoiesis controlled by transcription factor dosage.