Bone Marrow Specific Notch-IL21 Axis Primes and Expands Pre-Thymic T Cell Primed Lymphoid Progenitors

Long-term impairment in T cell mediated adaptive immunity is a major clinical obstacle after treatment of blood disorders with Hematopoietic Stem Cell Transplantation (HSCT). Although T cell development in the thymus has been extensively characterized, there are significant gaps in our understanding of the pre-thymic processes which influence early T cell potential. Recently, we and others have determined that the initial activation of the Notch signaling pathway, which is required for T cell development, occurs pre-thymically in Bone Marrow (BM) lymphoid progenitors. However, the downstream signaling events of Notch activation in BM progenitors in the context of T cell development are unknown. Here, we have uncovered a Notch-IL21 signaling axis which is involved in the priming of BM Common Lymphoid Progenitors (CLP) cells towards the T cell fate. IL21r expression is driven by Notch activation in CLPs, and in vivo treatment with IL21 induces Notch-dependent CLP proliferation. Taking advantage of this novel signaling axis, we have generated T cell progenitors ex vivo which better repopulate the thymus and peripheral lymphoid organs of mice in an allogeneic transplant model. Importantly, Notch and IL21 activation is equally effective in the priming and expansion of human cord blood cells toward the T cell fate, confirming the translational potential of the combined treatment. Therefore, Notch-IL21 treatment allows for the simultaneous T cell priming and rapid expansion of ex vivo derived T cell progenitors, which are therapeutically beneficial in improving T cell recovery post-HSCT.