Intestinal ILC progenitors differentially generate ILC subsets dependent on the recipient tissue microenvironment

Innate lymphoid cells (ILC) are critical in maintaining tissue homeostasis, and during infection and inflammation. Using combinatorial reporter mice we demonstrate the existence of rare, small intestinal lamina propria (siLP)- resident, ILC progenitors (siLP-ILCP) in adult mice. Transfer of siLP-ILCP into recipients generated ILC1/NK cells, ILC2 and ILC3 within the siLP microenvironment, but only ILC1/NK cells in the liver, lung and spleen. Single cell gene expression analysis confirmed the phenotype of the siLP-ILCPs and ILC progeny and indicated that siLP-ILCP-derived ILC1/NK cells from the siLP have a more tissue-resident phenotype than those from the lungs. Thus, in contrast to bone marrow-derived ILCPs, a local pool of siLP-ILCP can contribute to pan-ILC production in the intestinal microenvironment but has restricted potential in other tissues. Therefore, ILCP potential is influenced by both tissue of origin and the microenvironment during development. This may provide additional flexibility during the tuning of immune reactions. Comparative gene expression profiling analysis of RNA-seq data for newly identified siLP ILC progenitors compared to their in vivo progeny from the siLP and lung of immunocompromised recipients (Rag2-/-Il2rg-/-)