Multimodal Mapping of Human Lymphopoiesis Reveals B and T/NK/ILC Lineages are Subjected to Cell-Intrinsic versus Flt3L-Dependent Regulation

SUMMARY The developmental cartography of human lymphopoiesis remains incompletely understood. Here, we establish a multimodal map that extends the current view of lymphoid development. Our results demonstrate that lymphoid specification follows independent direct or stepwise differentiation pathways converging toward the emergence of CD117 lo multi-lymphoid progenitors (MLPs) that undergo a proliferation arrest before entering the CD127 - (T/NK/ILC) or CD127 + (B) lymphoid pathways. While the emergence of CD127 - early lymphoid progenitors is driven by Flt3 signaling, differentiation of their CD127 + counterparts is regulated cell-intrinsically and depends exclusively on the divisional history of their precursors. Single-cell mapping of lymphoid differentiation trajectories reveals that a dissociation between proliferation and differentiation phases allows amplification of the precursor pools prior to the onset of antigen receptor rearrangement. Besides demonstrating that B and T/NK/ILC lineages are subjected to differential cell-autonomous versus Flt3-inducible regulation, our results go a long way to reconciling human and mouse models of lymphoid architecture.