Tissue-selective chemoattractants direct lymphocytes to epithelial surfaces to establish local immune environments, regulate immune responses to food antigens and commensal organisms, and protect from pathogens. Homeostatic chemoattractants for small intestines, colon, and skin are known^{1 2}, but chemotropic mechanisms selective for respiratory tract and other non-intestinal mucosal tissues (NIMT) remain poorly understood. Here we leveraged diverse omics datasets to identify GPR25 as a lymphocyte receptor for CXCL17, a chemoattractant cytokine whose expression by epithelial cells of airways, upper gastrointestinal and squamous mucosae unifies the NIMT and distinguishes them from intestinal mucosae. Single-cell transcriptomic analyses show that GPR25 is induced on innate lymphocytes prior to emigration to the periphery, and is imprinted in secondary lymphoid tissues on activated B and T cells responding to immune challenge. GPR25 characterizes B and T tissue resident memory and regulatory T lymphocytes in NIMT and lungs in humans and mediates lymphocyte homing to barrier epithelia of the airways, oral cavity, stomach, biliary and genitourinary tracts in mouse models. GPR25 is also expressed by T cells in cerebrospinal fluid and CXCL17 by neurons, suggesting a role in CNS immune regulation. We reveal widespread imprinting of GPR25 on regulatory T cells, suggesting a mechanistic link to population genetic evidence that GPR25 is protective in autoimmunity^3,4. Our results define a GPR25-CXCL17 chemoaffinity axis with the potential to integrate immunity and tolerance at non-intestinal mucosae and the CNS.

组织选择性趋化因子将淋巴细胞引导至上皮表面，以建立局部免疫环境，调节对食物抗原和共生生物体的免疫反应，并防止病原体。已知用于小肠、结肠和皮肤的稳态趋化因子^{1 2}，但对呼吸道和其他非肠粘膜组织 （NIMT） 选择性的趋化机制仍然知之甚少。在这里，我们利用不同的组学数据集将 GPR25 鉴定为 CXCL17 的淋巴细胞受体，CXCL17 是一种趋化细胞因子，其气道、上消化道和鳞状粘膜上皮细胞的表达统一了 NIMT 并将其与肠粘膜区分开来。单细胞转录组学分析表明，GPR25 在迁移到外周之前在先天淋巴细胞上被诱导，并印记在响应免疫攻击的活化 B 细胞和 T 细胞的次级淋巴组织中。GPR25 表征人类 NIMT 和肺部中的 B 和 T 组织驻留记忆和调节性 T 淋巴细胞，并介导小鼠模型中淋巴细胞归巢到气道、口腔、胃、胆道和泌尿生殖道的屏障上皮细胞。GPR25 也由脑脊液中的 T 细胞表达，CXCL17 由神经元表达，表明在 CNS 免疫调节中发挥作用。我们揭示了 GPR25 在调节性 T 细胞上的广泛印记，表明与 GPR25 在自身免疫中具有保护作用的群体遗传证据存在机制联系^3,4。我们的结果定义了一个 GPR25-CXCL17 化学亲和轴，有可能整合非肠粘膜和 CNS 的免疫和耐受性。