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.