Stage-specific functions of E-proteins at the β-selection and T-cell receptor checkpoints during thymocyte development

The E-protein transcription factors E2A and HEB function in a lineage- and stage-specific manner to orchestrate many critical events throughout lymphocyte development. The function of E-proteins in both B- and T-lymphocyte development has been extensively studied through the use of single-gene knockout animals. Unlike B cells, which rely primarily on E2A alone, T cells are regulated by the combinatorial expression of both E2A and HEB. Therefore, many of the roles of E-proteins during T-cell development may be masked in single-gene knockout studies due to the compensatory function of E2A and HEB. More recently, our laboratory has established double-conditional knockout models to eliminate both E2A and HEB in a stage-specific manner throughout T-cell development. These models, in combination with other complimentary genetic approaches, have identified new E-protein functions at each of the two major T-cell developmental checkpoints. Here, we will discuss how E-proteins function to regulate the expression of T-cell receptor components and cell cycle at the β-selection checkpoint, and how they control positive selection, survival, and lineage-specific gene expression at the subsequent T-cell receptor checkpoint.