HEB in the Spotlight: Transcriptional Regulation of T-Cell Specification, Commitment, and Developmental Plasticity
Figure 1
Key transcription factors in early T-cell development. Regulation of early T-cell development occurs through the coordinated action of transcription factors. (a) GATA3 is important for the generation of DN1 cells, and GATA3−/− mice fail to produce any T-cells. Inactivation of GATA3 during DN stages results in a block at the DN3 stage due to defects in TCRβ expression. When GATA is inactivated at the later stages of T-cell development, no CD4 SP cells can be generated. Notch1 signalling is indispensable for T-cell specification and commitment since mice deficient in Notch1 give rise to intrathymic B cells at the expense of T cells. Notch1 inactivation during DN stages arrests T-cell development at the DN3 stage due to the defects in V-(D)J rearrangements of the TCRβ locus. Inactivation of TCF1 and LEF1 simultaneously results in the partial block at the DN3 stage and a complete block at the ISP stage as cells fail to rearrange TCRα locus. Lastly, Bcl11b is essential for the specification into the T-cell lineage. Bcl11b−/− cells fail to progress past the DN2 stage of T-cell development, and instead, differentiate into NK cells. (b) T-cell blocks associated with mutations in HEB, E2A and/or E2-2 E-proteins and their antagonists, Id1 and Id2. Solid blunt lines indicate complete developmental arrest, while dotted blunt lines indicate a partial developmental arrest. DN: double negative, DP: double positive, SP: single positive, ISP: immature single positive, NK: natural killer, B: B lymphocytes.
