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 with in vitro and in vivo functional 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.

在小鼠中建立的造血细胞经典模型假定淋巴细胞起源于常见淋巴祖细胞的建立者群体。在这里，使用人性化的小鼠模型方法，我们发现，人类淋巴发展从CD127的不同群体茎^-和CD127 ⁺早期淋巴祖（电子学习）。结合分子分析用在体外和体内功能性测定法，我们表明，CD127 ^-和CD127 ⁺ELPs独立于淋巴-单树突状祖细胞出现，对Notch1信号的反应不同，经历了谱系限制的不同模式，并显示出共同的和特定的分化潜能。CD127 ^- ELP包含T细胞，边缘区B细胞，自然杀伤（NK）和先天淋巴样细胞（ILC）的前体，而CD127 ⁺ ELP支持所有NK细胞，ILC和B细胞群的产生，但缺乏T潜能。在这些结果的基础上，我们提出了人类淋巴发育的“两族”模型，与流行的造血模型不同。