Within the thymus, Notch signals imprint T cell identity on multipotential hematopoietic progenitors. Notch signals must inhibit non-T cell fates (commitment) and drive T cell lineage-specific gene expression (specification), but the mechanisms have remained unclear. We recently identified T Cell Factor-1 (TCF-1) as the "missing link" that coordinates T-lineage specific gene expression downstream of Notch signals. We further discovered that HES-1 is important for establishing T cell commitment in early T cell progenitors. We propose to investigate molecular mechanisms through which TCF-1 and HES-1 establish and maintain T cell identity.
In Aim 1, we will examine how HES-1 and TCF-1 together establish commitment to the T cell lineage. Because TCF-1 continues to be expressed after T cell commitment, we will investigate whether T-cell specific gene expression unravels if TCF-1 is ablated in committed T cell progenitors.
In Aim 2, we will establish the mechanisms by which TCF-1 acts in T cell development. We will identify the gene regulatory program controlled by TCF-1, and we will identify and study partners that work with TCF-1 to control gene expression. Studies in this proposal will improve our understanding of how T cells are generated and how T cell identity is maintained. They may inform therapeutic strategies to boost T cell development and reconstitution in immune deficiency and after bone marrow transplantation.
Defects in T cell development may cause susceptibility to infections or leukemia development. We propose to identify the molecular mechanisms that control early T cell development. Our studies may lead to new therapeutic strategies to accelerate T-cell development in immune deficiency disorders and after bone marrow transplantation, and will also provide insights into how dysregulated T cell development can result in T cell leukemia.