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. Here, we show that helminth infection–induced redistribution of group 2 innate lymphoid cells (ILC2s) requires access to lymphatic vessels. Interleukin (IL)-25 signal induces a dramatic change in the epigenetic landscape of intestinal ILC2s, and transcription factors KLF2 and ZEB2 upregulate the expression of sphingosine-1-phosphate receptor 1 (S1PR1) and S1PR5, respectively. S1PR5 regulates ILC2 exit from the intestine to the lymph, whereas S1PR1 is critical for ILC2 egress from the mesenteric lymph nodes to the blood and then to distal tissues including the lung, where redistributed ILC2s contribute to tissue repair. The requirement of two S1PRs is largely due to the dynamic expression of CD69, which mediates S1PR1 internalization. These findings demonstrate that S1PRs modulate ILC2 emigration from nonlymphoid and lymphoid organs in a stage-specific manner, providing a framework for understanding the multistep migration of tissue-resident immune cells.