T-Lineage Specification and Commitment Requires Constraint of Myeloid Gene Expression Programs by Hes1

Early thymic progenitors (ETPs) are not committed to the T cell lineage; however, whether ETPs realize alternative (non T cell) lineage potentials in vivo is not well understood and indeed controversial. Notch signaling induces T cell lineage gene expression and discourages alternative fate outcomes; however, the mechanisms by which this occurs remain unclear. The work described here provides insight into two related questions in the field of early T cell development: first, we address whether ETPs adopt alternative fates in the thymus (Chapter 2) and second, we investigate the mechanisms used to constrain alternative gene expression programs as progenitors commit to the T cell lineage (Chapter 3 and 4). We found that ETPs do in fact access myeloid developmental fates in vivo, since the majority of thymic granulocytes appear to derive from ETPs. Next, we identified the Notch target and transcriptional repressor Hes1 as an important mechanism that constrains myeloid gene expression programs in T cell progenitors. Hes1 deficiency in hematopoietic progenitors severely compromises T cell development; however, this defect can be completely rescued by deletion of the myeloid regulator C/EBPα. Thus, our findings indicate that ETPs are bona fide myelo-lymphoid progenitors and establishes the critical importance of constraining myeloid developmental programs early in T cell development.