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

Authors: ITO, TAKAMASA - Columbia University Medical Center; WU, CHRISTINE - Columbia University Medical Center; ZHANG, YINGYU - Columbia University Medical Center; ISHIDA, YOSHIHIRO - Kyoto University; GRETARSSON, KRISTJAN - Columbia University Medical Center; XU, XINJING - Columbia University Medical Center; ZOU, RAYMOND - Columbia University Medical Center; GUICHARD, VINCENT - Columbia University Medical Center; HUANG, LEI - Columbia University Medical Center; HAN, RICHARD - Columbia University Medical Center; GUCKIAN, KEVIN - Biogen; CHUN, JEROLD - Sanford And Burnham Medical Research Institute; QUE, JIANWEN - Columbia University Medical Center; Smith, Allen; Urban Jr, Joseph; LU, CHAO - Columbia University Medical Center; HUANG, YUEFENG - Columbia University Medical Center

Submitted to: Science Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/27/2026
Publication Date: 3/13/2026
Citation: Ito, T., Ishida, Y., Zhang, Y., Guichard, V., Huang, L., Han, R., Smith, A.D., Urban Jr, J.F., Huang, Y., Guckian, K., Chun, J., Que, J., Wu, C., Gretarsson, K., Xu, X., Zou, R., Lu, C. 2026. Inflammatory ILC2s migrate to distal tissues during infection using stage-specific S1P receptors. Science Immunology. 11(117):1-18. HTTPS://doi.org/10.1126/sciimmunol.adw4613.
DOI: https://doi.org/10.1126/sciimmunol.adw4613

Interpretive Summary: White blood cells called lymphocytes can circulate in the blood as well as reside within tissues. While the mechanisms by which circulating lymphocytes are recruited to infection sites have been extensively characterized, the molecular basis for the recirculation of tissue-resident cells is less understood. Here, we show that a parasitic worm infection- or giving IL-25, an immune molecule important for controlling worm infections, causing redistribution of intestinal group 2 innate lymphoid cells (ILC2s), requires access to the lymphatic system is redundant for ILC2 migration and effector function. In contrast, the lymphatic system is an essential signal hub for adaptive lymphocyte differentiation and movement. The IL-25 signal induces a dramatic change to a specific kind of gene modification called epigenic changes in intestinal ILC2s, enabling the expression of a group of proteins called sphingosine-1-phosphate (S1P) receptors. S1PR5 is critical for ILC2 leaving intestinal tissue and into the lymph system, while S1PR1 plays a dominant role in ILC2 leaving mesenteric lymph nodes and going into blood circulation and then to distal sites including the lung, where the redistributed ILC2s contribute to repairing damaged tissue. The requirement of two S1PRs is largely due to the dynamic expression of a protein called CD69, which prompts S1PR1 internalization, a signal necessary ILC2 cells to migrate. Thus, our study demonstrates a stage-specific requirement of different S1P receptors for ILC2 movement during infection and we propose a model in which innate and adaptive lymphocytes utilize shared circulatory pathways and specialized navigation cues for their migration. This study increases our understanding of how our immune system responds to parasitic worm infection.

Technical Abstract: 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.