美国斯坦福大学医学院Borja Ocón，Menglan Xiang和Yuhan Bi共同合作，近期取得重要工作进展。他们研究发现了肺、非肠粘膜和中枢神经系统的淋巴细胞趋化亲和轴。相关研究成果2024年9月18日在线发表于《自然》杂志上。

据介绍，组织选择性化学引诱剂将淋巴细胞引导到上皮表面，以建立局部免疫环境，调节对食物抗原和共生生物的免疫反应，并保护其免受病原体的侵害。小肠、结肠和皮肤的稳态趋化剂是已知的，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。

研究人员利用不同的组学数据集将GPR25鉴定为CXCL17的淋巴细胞受体，CXCL17是一种化学引诱细胞因子，其在气道、上消化道和鳞状上皮细胞中的表达将NIMT统一起来，并将其与肠粘膜区分开来。单细胞转录组分析表明，GPR25在迁移到外周之前在先天淋巴细胞上被诱导，并在次级淋巴组织中印迹在对免疫挑战有反应的活化B和T细胞上。

GPR25表征了人类NIMT和肺部的B和T组织驻留记忆和调节性T淋巴细胞，并在小鼠模型中介导淋巴细胞归巢至气道、口腔、胃、胆道和泌尿生殖道的屏障上皮。GPR25也由脑脊液中的T细胞表达，CXCL17由神经元表达，表明其在中枢神经系统免疫调节中起作用。研究人员揭示了GPR25在调节性T细胞上的广泛印记，这表明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。

总之，这一研究结果确定了GPR25-CXCL17趋化亲和轴，该轴有可能整合非肠道粘膜和中枢神经系统的免疫和耐受性。

附：英文原文

Title: A lymphocyte chemoaffinity axis for lung, non-intestinal mucosae and CNS

Author: Ocn, Borja, Xiang, Menglan, Bi, Yuhan, Tan, Serena, Brulois, Kevin, Ayesha, Aiman, Kunte, Manali, Zhou, Catherine, LaJevic, Melissa, Lazarus, Nicole, Mengoni, Francesca, Sharma, Tanya, Montgomery, Stephen, Hooper, Jody E., Huang, Mian, Handel, Tracy, Dawson, John R. D., Kufareva, Irina, Zabel, Brian A., Pan, Junliang, Butcher, Eugene C.

Issue&Volume: 2024-09-18

Abstract: 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 known1 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 autoimmunity3,4. Our results define a GPR25-CXCL17 chemoaffinity axis with the potential to integrate immunity and tolerance at non-intestinal mucosae and the CNS.

DOI: 10.1038/s41586-024-08043-2

Source: https://www.nature.com/articles/s41586-024-08043-2