Single-cell RNA-sequencing of human lung innate lymphoid cells in the vascular and tissue niche reveals molecular features of tissue adaptation

Abstract Innate lymphoid cells (ILCs) are sentinels of healthy organ function, yet it is unknown how ILCs adapt to distinct anatomical niches within tissues. Here, we used a unique humanized mouse model, MISTRG mice transplanted with human hematopoietic stem and progenitor (HSPCs), define the gene signatures in vascular versus tissue (extravascular) compartment lung. Single-cell RNA-sequencing combination intravascular cell labeling demonstrated that heterogeneous populations natural killer (NK) occupied lung HSPC-engrafted mice. Moreover, discovered niche-specific cues shape molecular programs sub-anatomical compartments Specifically, extravasation into was associated upregulation genes involved acquisition residency, positioning lung, sensing tissue-derived signals, cellular stress responses, nutrient uptake, interaction other tissue-resident immune cells. We also defined core signature shared between NK extravascular space consistent imprinting by signals from local microenvironment. The characterization provides new knowledge on mechanisms ILC adaptation represents resource for further studies.