Dynamic Regulation of Innate Lymphoid Cell Development During Ontogeny

Innate lymphoid cells (ILCs) are crucial for maintaining tissue homeostasis. The dynamic composition of ILC subsets during ontogeny has been observed for over a decade, yet the underlying mechanisms remain incompletely understood. Here, we combined differentiation assay and scRNA-seq analysis to compare the fetal and adult ILC development, and assessed their contribution to the dynamic change of ILC subsets. We revealed the preference for LTi cell differentiation in fetal hematopoietic progenitors, contrasted with a non-LTi differentiation bias in adult stages. Our analyses elucidated that the two stages shared a conserved differentiation trajectory and regulatory programs but used different controlling logic. Through computational prediction and dose-response experiments, we proposed a model where a transition from fetal ROR{gamma}t-dominant states to adult Notch-GATA3-dominant states orchestrates these changes. This study suggests that ILC development can be modulated to accommodate the varying demands for specific ILC subsets within the body at different developmental stages. HighlightO_LIThe ratio of LTi cells to non-LTi ILCs decreases from fetal to adult stage C_LIO_LIModified fate determination of ILC progenitors contributes to this decrease of LTi cell ratio during ontogeny C_LIO_LIA conserved trajectory exists from early LPs to Innate Lymphoid Cell Precursors (ILCPs) during both fetal and adult ILC development C_LIO_LIEnhanced activity of Notch-GATA3 signaling in ILC precursors accounts for the transition of their differentiation from LTi cells in the fetal to non-LTi ILCs in adults. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=181 SRC="FIGDIR/small/565141v2_ufig1.gif" ALT="Figure 1"> View larger version (85K): org.highwire.dtl.DTLVardef@11a031eorg.highwire.dtl.DTLVardef@c2d652org.highwire.dtl.DTLVardef@184cdfeorg.highwire.dtl.DTLVardef@1efe7ae_HPS_FORMAT_FIGEXP M_FIG C_FIG