A Role for Notch Signaling in Lymphoid Progenitor Development in the Bone Marrow

Abstract

A major clinical obstacle after treatment of blood disorders with hematopoietic stem cell transplantation (HSCT) is the resultant long‐term impairment in T cell mediated adaptive immunity. Though T cell development in the thymus has been extensively characterized, there are significant gaps in our understanding of pre‐thymic T cell commitment. The Notch pathway is vital for the development of T cell progenitors in the thymus. We have confirmed a role for Notch signaling in the bone marrow Common Lymphoid Progenitor (CLP) population which suggests that Notch signals may instruct lymphoid progenitors towards the T cell fate even before exiting the bone marrow. Using a genetic Notch1 hypomorhic mouse model, we find defective T cell lineage development as early as the CLP, with no defect in B cell or NK cell development downstream of the CLP. We further generated a list of genes dependent on Notch signaling within the CLP population using RNA sequencing. One downstream target of Notch in CLPs is IL21r, which we have confirmed plays a role in the proliferation of Notch activated CLP cells in the bone marrow. Our work uncovers a T cell lineage developmental pathway initiated by Notch signaling in the bone marrow CLP population.