Inflammatory ILC2s migrate to distal tissues during infection using stage-specific S1P receptors.

Tissue-resident lymphocytes can recirculate, but the underlying molecular mechanism is poorly understood. During helminth infection, intestinal group 2 innate lymphoid cells (ILC2s) rapidly proliferate and give rise to inflammatory ILC2s (iILC2s), which migrate from the intestine to distal tissues. Here, we show in mice that the redistribution of iILC2s requires access to lymphatic vessels. Interleukin-25 (IL-25) induces a substantial change in the epigenetic landscape of iILC2s, with transcription factors KLF2 and ZEB2 driving increased expression of sphingosine-1-phosphate receptor 1 (S1PR1) and S1PR5, respectively. S1PR5 regulates iILC2 exit from the intestine to the lymph, whereas S1PR1 is critical for iILC2 egress from the mesenteric lymph nodes to the blood and then to distal tissues including the lung, where iILC2s contribute to tissue repair. The requirement of two S1PRs is largely due to the dynamic expression of CD69, which mediates S1PR1 internalization. Thus, S1PRs modulate iILC2 emigration from nonlymphoid and lymphoid organs in a stage-specific manner, which provides a framework for understanding the multistep migration of tissue-resident immune cells.