Establishment of lympho-myeloid restricted progenitors prior to the emergence of definitive hematopoietic stem cells

In jawed vertebrates, development of an adaptive immune-system is essential for protection of the born organism against otherwise life-threatening pathogens. Myeloid cells of the evolutionary older innate immune-system are formed early in development, while lymphopoiesis has been suggested to initiate much later, following emergence of definitive hematopoietic stem cells (HSCs). Herein, we prospectively identified a lympho-myeloid restricted embryonic progenitor as early as E11.5 that expresses IL7Rα and that sustains combined lymphoid and GM transcriptional lineage priming and lineage potentials at the single cell level but no MkE potential. Using Rag1-GFP knock-in mice, we tracked the establishment of this lympho-myeloid restricted progenitor back to as early as E9.5, preceding both hematopoietic colonization of the FL and the establishment of definitive HSCs. Moreover, through in vivo fate mapping we confirmed the inability of Rag1 expressing early embryonic progenitors to contribute to the MkE lineage, while unequivocally and robustly contributing to the myeloid innate as well as lymphoid adaptive immune systems of the mammalian embryo. These findings identify the developmentally earliest immune-restricted progenitor and establish the lympho-myeloid restriction step as a physiologically important lineage commitment step in embryonic mammalian hematopoiesis, preceding the emergence of definitive HSCs.