Hes1-mediated constraint of C/EBPα is essential for T-cell development (111.22)

Abstract

Abstract Notch signaling in the thymus induces expression of T-cell genes and discourages progenitors from adopting alternative fates. Recent work has suggested that T-cell progenitors arrive at the thymus with T and non-T (B, NK) lymphoid potential as well as dendritic cell potential and a degree of myeloid potential; however, the importance of actively repressing alternative gene expression programs in T-cell development has not been adequately addressed. To examine the role of Notch-mediated gene repression in T-cell development, we used mice deficient for the Notch target and transcriptional repressor Hes1. We found that Hes1-deficient progenitors failed to make normal numbers of T-cells upon culture with Notch ligands, but instead failed to downregulate the myeloid transcription factor C/EBPα and gave rise to increased numbers of Mac1+ myeloid cells. To test whether the primary role of Hes1 in T-cell development is to repress expression of the myeloid transcription factor C/EBPα, we deleted floxed alleles of C/EBPα in Hes1-deficient progenitors using a retroviral Cre recombinase and co-cultured transduced progenitors with Notch-ligand expressing stromal cells. We found that deletion of C/EBPα restored T-cell development in Hes1-deficient progenitors. These results establish that an essential function of Hes1 is to constrain progenitors from activating myeloid lineage programs early in T-cell development.