LAUSR

Literature Watch 2669 R E P R IN TE D F R O M IM M U N IT Y, 5 0: 6, 2 01 9, 1 42 5– 38 , W IT H P E R M IS S IO N F R O M E LS E V IE R . Innate lymphoid cells (ILCs) are an immune subset wedged between the innate and adaptive immune systems. They harbor preformed cytokines like innate immune cells and do not possess a rearranged antigen-specific receptor like adaptive T and B cells; however, they subdivide into ILC1, ILC2 and ILC3 subsets that resemble effector T helper 1 (Th1), Th2 and Th17 cells, respectively. Similar to tissueresident memory T cells, ILCs are thought to infiltrate peripheral tissues in a sessile manner and contribute to tissue homeostasis and local immunity. ILC2s in particular may participate in antihelminth and allergic responses traditionally associated with Th2 cells. The contribution of embryonic versus postnatal progenitors to tissue ILCs is not known. Determining whether they generate transcriptionally distinct subsets may provide clues as to the role of ILC2s at steady state and during inflammation. The authors use fate-mapping in mice and identify three waves of ILC2 tissue infiltration: fetal-, neonataland adult-derived, with neonatal expansion coinciding with activation and acquisition of tissue-specific transcriptional signatures and giving rise to an antihelminth response in adults. The development of ILCs depends on the transcription factor Id2 and the cytokine receptor IL-7Rα. Additionally, several ILC precursors express the urea cycle enzyme Arg 1, although this is not exclusive to ILC2s. The authors use Id2-CreER and Arg1CreER crossed to R26R-EYFP and R26R-RFP reporter mice as two complementary fate-mapping approaches to mark ILC2s (defined as Lin-IL7Rα+Thy1+ST2+) post administration of tamoxifen. Fate-mapping of ILC2s in adult mice showed a low rate of ILC2 replacement in tissue, although the rate was faster in skin and bone marrow. Parabiosis experiments between fate-mapped and partner mice confirmed that ILC2s do not recirculate, or even populate empty niches at steady state in IL7Rα-deficient partners that lack ILCs and T and B cells. Arg1 fate-mapping of ILC2 precursors during embryonic days E16.5 to E18.5 revealed an embryonic origin of approximately 5 to 10% of ILC2s at 2 months of age in the lung, small intestine and visceral adipose fat, whereas none of the bone marrow cells remained labeled in the adult. In mice that received tamoxifen on days 10 to 12 after birth, 40 to 70% of labeled ILC2s were still found in the adult lung, small intestine, fat and skin, but did not persist in the bone marrow. This neonatal wave was accompanied by IL-7Rα–dependent activation and cytokine acquisition and expansion. The neonatal period coincides with colonization with microbiota, but ILC2 expansion was similar in the control and germ-free mice. Single-cell RNA sequencing demonstrated greater activation of neonatal ILC2s than adult ILC2s, and distinct tissue-specific expression profiles shared between neonatal and adult ILC2s. Finally, adult infection with the helminth Nippostrongylus brasiliensis did not reduce the proportion of postnatally fate-mapped ILC2s despite an 8-fold expansion in the lungs and small intestine. Thus, tissue ILC2s primarily derive during early postnatal development and expansion, acquire tissue-defining gene expression profiles and respond to inflammation, rather than newly generated ILC2s from hematopoietic precursors. Whether ILC2s derived from embryonic versus early postnatal or adult progenitors have different gene expression and function remains to be determined. ILC2s have been implicated in renal homeostasis and repair and have thus been suggested as a possible cell therapy for acute kidney injury. In hematopoietic stem cell transplantation, host ILC3s that are resistant to myeloablative conditioning are thought to maintain intestinal barrier function and prevent graft-versus-host disease. Importantly, donor-resident ILCs have been reported to persist more than 8 years after human intestinal transplantation. Nevertheless, little is known about the role of ILCs in transplantation, most notably because of the difficulty in eliminating them selectively. One could use the fate-mapping approach developed by Schneider and colleagues to first determine whether ischemia-reperfusion injury and acute or chronic rejection associate with expansion of donor (or recipient) ILC2s, especially after lung transplantation, as these cells may contribute to overzealous repair and chronic rejection. Additionally, the approach could be used to mark donor ILC2s with diphtheria toxin receptor rather than fluorescent proteins, which would enable their depletion at different time points after transplantation and probe their requirement.