Multimodal Mapping of Human Lymphopoiesis Reveals B and T/NK/ILC Lineages are Subjected to Cell-IntrinsicversusFlt3L-Dependent Regulation

Abstract

SUMMARYThe 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 CD117lomulti-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-autonomousversusFlt3-inducible regulation, our results go a long way to reconciling human and mouse models of lymphoid architecture.