Abstract
Circulating group 2 innate lymphoid cells (ILC2s) comprise a third of all lung ILC2s shortly after helminth infection, providing an early source of type-2 cytokines. However, the origin of circulating ILC2s and their relationship with ILC progenitors and tissue-resident ILC2s remain unresolved. Single-cell RNA-sequencing and trajectory analysis of ILC2 and ILC2 progenitors in the lung, bone marrow (BM), and intestine draining lymph nodes (LNs) revealed that circulating ILC2s in the lung mirror a population of ILC2s in the mesenteric LNs. Conversely, lung-resident ILC2s closely resembled BM ILC progenitors. These BM progenitors gave rise to lung-resident ILC2s but not circulating ILC2s after adoptive transfer. Definitive proof of an intestinal origin for circulating ILC2s in the lung was achieved through in vivo photoconversion of the intestine. These findings emphasize how rapid deployment of intestinal ILC2s to distal sites of type-2 inflammation bolsters barrier immunity to allow time for tissue-resident ILC2 expansion.