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

Figure 4

Gene regulatory network model operating in early T-cell development. E2A positively regulates Notch1 expression, which induces the expression of HEBAlt, Bcl11b, and IL7R. HEBAlt positively regulates T-cell genes, such as pTα and Notch3, which in turn upregulates NF-κB signaling. Bcl11b negatively regulates Id2 and Gfi1b to balance the expression of GATA3, thus limiting the NK-cell potential. HEBAlt may also regulate GATA3 indirectly through Gfi1b. HEBAlt and Notch1 upregulate pTα and TCRβ, the components of pre-TCR, thus promoting transition from the DN2 to the DN3 stage of T-cell development. Pre-TCR signaling upregulates Id3, which inhibits the activity of E2A and HEBAlt at the β-selection checkpoint. The inhibition of HEBAlt activity past the DN3 stage is important as it disrupts the positive feedback loop between Notch3 and NF-κB, which may, otherwise, lead to leukemogenesis. Green arrows show positive inputs, red blunt arrows show negative inputs. Established connections are shown by solid arrows, and indirect or proposed connections are shown by dashed arrows.