The classical model of hematopoiesis established in the mouse postulates that lymphoid cells originate from a founder population of common lymphoid progenitors. Here, using a modeling approach in humanized mice, we showed that human lymphoid development stemmed from distinct populations of CD127− and CD127+ early lymphoid progenitors (ELPs). Combining molecular analyses within vitroandin vivofunctional assays, we demonstrated that CD127− and CD127+ ELPs emerged independently from lympho-mono-dendritic progenitors, responded differently to Notch1 signals, underwent divergent modes of lineage restriction, and displayed both common and specific differentiation potentials. Whereas CD127− ELPs comprised precursors of T cells, marginal zone B cells, and natural killer (NK) and innate lymphoid cells (ILCs), CD127+ ELPs supported production of all NK cell, ILC, and B cell populations but lacked T potential. On the basis of these results, we propose a “two-family” model of human lymphoid development that differs from the prevailing model of hematopoiesis.
The development pathways of human lymphoid cells remain unclear. Alhaj Hussen et al. show that human lymphoid cells stem from two functionally specialized populations of CD127− and CD127+ early lymphoid progenitors. They propose a “two-family” model of human lymphopoiesis that differs from the standard model of hematopoiesis established in mice.