Acquisition of a functional T cell receptor during T lymphocyte development is enforced by HEB and E2A transcription factors

The T cell receptor (TCR) is required for positive selection and the subsequent transition from the CD4(+)CD8(+) double-positive (DIP) to the CD4(+) or CD8(+) single-positive (SP) stage of alpha beta T cell development. The molecular mechanism that maintains DID fate prior to the acquisition of a functional TCR is not clear. We have shown here that the structurally and functionally related transcription factors HEB and E2A work together to maintain DID fate and to control the DID to SP transition. Simultaneous deletion of HEB and E2A in DIP thymocytes was sufficient for DIP to SP transition independent of TCR. Loss of HEB and E2A allowed DP cells to bypass the requirement for TCR-mediated positive selection, downregulate DP-associated genes, and upregulate SP-specific genes. These results identify HEB and E2A as the gatekeepers that maintain cells at the DID stage of development until a functional alpha beta TCR is produced.