An essential role for the transcription factor HEB in thymocyte survival, Tcra rearrangement and the development of natural killer T cells

Lymphocyte development requires transcription factors of the E2A family. Goldrath and colleagues identify a unique role for the E2 protein HEB in the generation and survival of invariant natural killer T cells. E proteins are basic helix-loop-helix transcription factors that regulate many key aspects of lymphocyte development. Thymocytes express multiple E proteins that are thought to provide cooperative and compensatory functions crucial for T cell differentiation. Contrary to that, we report here that the E protein HEB was uniquely required at the CD4 + CD8 + double-positive (DP) stage of T cell development. Thymocytes lacking HEB showed impaired survival, failed to make rearrangements of variable-α (V α ) segments to distal joining-α (J α ) segments in the gene encoding the T cell antigen receptor α-chain ( Tcra ) and had a profound, intrinsic block in the development of invariant natural killer T cells ( i NKT cells) at their earliest progenitor stage. Thus, our results show that HEB is a specific and essential factor in T cell development and in the generation of the i NKT cell lineage, defining a unique role for HEB in the regulation of lymphocyte maturation.