S1P-dependent interorgan trafficking of group 2 innate lymphoid cells supports host defense

Inflammatory ILC2s are itinerant sentinels Group 2 innate lymphoid cells (ILC2s) are a population of immune cells that play important roles in tissue homeostasis and barrier immunity to helminths. Recent work has suggested that ILC2s are primarily long-term residents of tissues that do not readily recirculate. Huang et al. now demonstrate, however, that these findings do not necessarily hold true for the interleukin-25 (IL-25)–responsive KLRG1hi “inflammatory” ILC2 (iILC2) subset (see the Perspective by Mjösberg and Rao). In response to exogenous IL-25 or helminth infection, iILC2 precursors in the small intestinal lamina propria proliferate and alter their expression of sphingosine 1-phosphate (S1P) receptors. They then traffic to both lymphatic and nonlymphatic organs in a partly S1P-dependent manner, participating in vital anti-helminth and tissue repair responses. Science, this issue p. 114; see also p. 36 Innate lymphoid cells complement adaptive immunity by providing both local and distant tissue protection during infection. Innate lymphoid cells (ILCs) are innate counterparts of adaptive T lymphocytes, contributing to host defense, tissue repair, metabolic homeostasis, and inflammatory diseases. ILCs have been considered to be tissue-resident cells, but whether ILCs move between tissue sites during infection has been unclear. We show here that interleukin-25– or helminth-induced inflammatory ILC2s are circulating cells that arise from resting ILC2s residing in intestinal lamina propria. They migrate to diverse tissues based on sphingosine 1-phosphate (S1P)–mediated chemotaxis that promotes lymphatic entry, blood circulation, and accumulation in peripheral sites, including the lung, where they contribute to anti-helminth defense and tissue repair. This ILC2 expansion and migration is a behavioral parallel to the antigen-driven proliferation and migration of adaptive lymphocytes to effector sites and indicates that ILCs complement adaptive immunity by providing both local and distant tissue protection during infection.