Impact of transcription factors E2-2, HEB and E2A in lymphoid development

The E-protein family of transcription factors consists of E2-2, HEB and E2A in the Gnathostomata. All three E-proteins impact lymphoid development while only E2A governs HSC function and the ancestral myeloid- and erythro/megakaryocytic lineages. However, the potential role of E2-2 in stem/progenitor cells and codependences of E2-2 with the evolutionarily related HEB remain to be explored. Here we show that disruption of E2-2 impaired the LY6D- to LY6D+ CLP transition, resulting in reduced B-cell numbers. The additional deletion of HEB resulted in a failure to express the early lymphoid program and a near complete block of the B-cell development at the LY6D- CLP stage. Additionally, the few generated transitional B-cells preferentially develop into marginal zone B-cells. T-cell development was also found to be perturbed with reduced CD4 T-cells and increased ?d T-cells. In the thymus, ETPs were reduced and T-cell development was perturbed, resulting in reduced CD4 T-cells and increased ?d T-cells. In contrast, HSCs, erythro-myeloid progenitors and innate immune cells were unaffected. Together, these suggest that E2-2 and HEB are dispensable for the ancestral hematopoietic lineages and that the appearance of the full Gnathostomata E-protein repertoire promoted the emergence of humoral immunity.