Nonimmune cells can have immunomodulatory roles that contribute to healthy development. However, the molecular and cellular mechanisms underlying the immunomodulatory functions of erythroid cells during human ontogenesis remain elusive. Here, integrated, single-cell transcriptomic studies of erythroid cells from the human yolk sac, fetal liver, preterm umbilical cord blood (UCB), term UCB and adult bone marrow (BM) identified classical and immune subsets of erythroid precursors with divergent differentiation trajectories. Immune-erythroid cells were present from the yolk sac to the adult BM throughout human ontogenesis but failed to be generated in vitro from human embryonic stem cells. Compared with classical-erythroid precursors, these immune-erythroid cells possessed dual erythroid and immune regulatory networks, showed immunomodulatory functions and interacted more frequently with various innate and adaptive immune cells. Our findings provide important insights into the nature of immune-erythroid cells and their roles during development and diseases.

非免疫细胞可以具有有助于健康发育的免疫调节作用。然而，人类个体发生过程中红系细胞免疫调节功能的分子和细胞机制仍然不清楚。在这里，来自人卵黄囊、胎儿肝脏、早产脐带血 (UCB)、足月 UCB 和成人骨髓 (BM) 的红系细胞的综合单细胞转录组学研究确定了具有不同分化轨迹的红系前体细胞的经典和免疫亚群. 在整个人类个体发育过程中，免疫类红细胞从卵黄囊一直存在到成年 BM，但未能在体外从人类胚胎干细胞中产生。与经典红细胞前体相比，这些免疫红细胞具有双重红细胞和免疫调节网络，显示出免疫调节功能，并更频繁地与各种先天性和适应性免疫细胞相互作用。我们的研究结果为免疫红细胞的性质及其在发育和疾病过程中的作用提供了重要的见解。