Inhibitors of DNA Binding Proteins Restrict T Cell Potential by Repressing Notch1 Expression in Flt3-Negative Common Lymphoid Progenitors

Lineage commitment is regulated during hematopoiesis, with stepwise loss of differentiation potential ultimately resulting in lineage commitment. In this study we describe a novel population of B/NK bipotent precursors among common lymphoid progenitors in the fetal liver and the bone marrow. The absence of T cell precursor potential, both in vivo and in vitro, is due to low Notch1 expression and secondary to inhibition of E2A activity by members of the inhibitor of DNA binding (Id) protein family. Our results demonstrate a new, Id protein-dependent, molecular mechanism of Notch1 repression, operative in both fetal and adult common lymphoid progenitors, where T cell potential is selectively inhibited without affecting either the B or NK programs. This study identifies Id proteins as negative regulators of T cell specification, before B and NK commitment, and provides important insights into the transcriptional networks orchestrating hematopoiesis. The Journal of Immunology, 2012, 189: 3822-3830.