HEBAlt enhances the T-cell potential of fetal myeloid-biased precursors

Abstract

Hematopoiesis is controlled by the interplay between transcription factors and environmental signals. One of the primary determinants of the T-lineage choice is Delta-like (DL)-Notch signaling, which promotes T-cell development and inhibits B-cell development. We have found that the transcription factor HEBAlt is up-regulated in early hematopoietic precursors in response to DL-Notch signaling and that it can promote early T-cell development. Here, we identified a population of lineage-negative Sca-1⁻c-kit(+) (LK) cells in the mouse fetal liver that rapidly gave rise to myeloid cells and B cells but exhibited very little T-cell potential. However, forced expression of HEBAlt in these precursors restored their ability to develop into T cells. We also showed that Ikaros and Notch1 are up-regulated in response to HEBAlt over-expression and that activated Notch1 enhances the ability of LK cells to enter the T-cell lineage. Furthermore, the myeloid transcription factor C/EBPα is down-regulated in response to HEBAlt. We therefore propose that HEBAlt plays a role in the network that enforces the T-lineage fate and limits myeloid fate during hematopoiesis.

Downregulation of the transcription factor KLF4 is required for the lineage commitment of T cells

“…HEBAlt, a long form of the E protein HEB gene, is specifically expressed in lymphoid precursor cells [34]. In thymic precursors, HEBAlt collaborates with Notch signals to promote early T cell development by suppressing B cell or myeloid potential [35][36]. HEB −/− T cells possess compromised Notch1 function and lose T cell potential [37].…”

An Overview of the Intrathymic Intricacies of T Cell Development

“…A developmental block in HEB 2/2 cells observed at the b-selection checkpoint can be partially restored with transgenic expression of HEBAlt, bypassing b-selection, to the DP stage, thus implicating HEBAlt as a critical regulator of early T-lineage genes (45). In addition, HEBAlt limits myeloid cell outcomes by collaborating with intracellular Notch (46). Furthermore, HEB 2/2 cells that have compromised Notch1 activity retain lineage plasticity, producing a DN1-like phenotype that could be induced to develop into NK cells and expresses Gata3 and Id2 but had lower levels of Bcl11b, a putative Notch target gene (47), suggesting that the canonical form of HEB is important for inhibiting NK cell fate.…”

HEB in the Spotlight: Transcriptional Regulation of T-Cell Specification, Commitment, and Developmental Plasticity

“…During B-cell development, HEBAlt overexpression suppressed B-cell potential, even in the absence of DL-Notch1 signals [111]. Lastly, HEBAlt was also shown to play a role in lympho-myeloid specification since precursors with a strong myeloid potential adopted the T-cell fate upon overexpression of HEBAlt [112]. However, the precise mechanisms by which HEBAlt guides T-cell development and fate choice remain to be determined.…”