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.

组织驻留淋巴细胞（tissue-resident lymphocytes）虽具备循环能力，但其背后的分子机制仍有待阐明。本研究证实，蠕虫感染诱导的2型先天淋巴细胞（group 2 innate lymphoid cells, ILC2s）重分布过程，依赖于淋巴管通路。白细胞介素-25（Interleukin, IL-25）信号可引发肠道ILC2s的表观遗传景观发生显著改变，转录因子KLF2与ZEB2分别上调鞘氨醇-1-磷酸受体1（sphingosine-1-phosphate receptor 1, S1PR1）与鞘氨醇-1-磷酸受体5（S1PR5）的表达。其中，S1PR5可调控ILC2从肠道向淋巴液的迁出，而S1PR1则对ILC2从肠系膜淋巴结（mesenteric lymph nodes）迁出至血液、进而抵达包括肺脏在内的远端组织至关重要；重分布至肺脏的ILC2s可参与组织修复过程。两种S1PR的功能需求，主要源于介导S1PR1内吞作用的CD69的动态表达。本研究结果表明，S1PRs可通过阶段特异性方式调控ILC2从非淋巴器官与淋巴器官的迁出，为理解组织驻留免疫细胞的多步骤迁移过程提供了理论框架。