Innate Lymphoid Cells Originate from Fetal Liver-Derived Tissue-Resident Progenitors

Committed progenitors with innate lymphoid cell (ILC) developmental potential are present in the fetus and bone marrow (BM). However, how fetal and BM hematopoiesis temporally and spatially contributes to ILC pools remains unclear. Here, we elucidated the distinct origins and developmental pathways of extramedullary and intramedullary ILCs during ontogeny. ILC-restricted hematopoiesis is initiated in the fetal liver (FL) and then FL-derived PD-1+ ILC progenitors (ILCPs) seed fetal lung and intestine. Organ niches determine the commitment of ILCPs to downstream precursors, including bipotent ILC1-ILC3 precursors (ILC1/3Ps) that are preferentially residing in the liver and intestine and ILC2 precursors (ILC2Ps) that show predominance in the lung. These precursors persist in adulthood and contribute to local ILC pools via BM-independent manner. In contrast, intramedullary ILC2Ps and ILC2s rely on BM hematopoiesis. Thus, our study highlights extramedullary and intramedullary ILCs with different origins, providing a comprehensive framework for developmental dynamics of ILCs. Lin−CD45+CD127+Flt3−α4β7+CD25− α4β7-expressing progenitors (αLPs) were sorted from E14.5 fetal liver and adult bone marrow tissues respectively of WT mice for single-cell RNA sequencing (scRNA-seq).