Dynamic Regulation of Innate Lymphoid Cell Development During Ontogeny

Abstract

SUMMARYInnate 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 RORγt-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.HighlightThe ratio of LTi cells to non-LTi ILCs decreases from fetal to adult stageModified fate determination of ILC progenitors contributes to this decrease of LTi cell ratio during ontogenyA conserved trajectory exists from early αLPs to Innate Lymphoid Cell Precursors (ILCPs) during both fetal and adult ILC developmentEnhanced 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.Graphical abstract