The opposing roles of E2A and Id3 that orchestrate and enforce the naïve T cell fate

It is established that E2A and its antagonist, Id3, modulate developmental progression at the pre-TCR receptor (pre-TCR) and TCR checkpoints. Here we demonstrate that Id3 expression is elevated beyond the pre-TCR checkpoint, remains high in naive T cells and shows a bimodal pattern in the effector/memory population. We show how E2A promotes T-lineage specification and how pre-TCR mediated signaling affects E2A genome-wide occupancy. Thymi in Id3-deficient mice exhibited aberrant development of effector/memory cells, increased CXCR5 and Bcl6 expression, T-B cell conjugates and remarkably B cell follicles. Collectively, these data show how E2A acts globally to orchestrate T-lineage development and that Id3 antagonizes E2A activity beyond the pre-TCR checkpoint to enforce the naïve T cell fate.