Shao Tiange, Yao Jiacheng, Hou Shiyue, Wang Jianbin, Qi Hai
Laboratory of Dynamic Immunobiology, Institute for Immunology, Tsinghua University, Beijing, 100084, China.
School of Basic Medical Sciences, Tsinghua Medicine, Tsinghua University, Beijing, 100084, China.
Sci China Life Sci. 2025 May 30. doi: 10.1007/s11427-024-2920-y.
Tissue-resident memory T cells (T) play a key role in defense against pathogen invading barrier sites and other non-lymphoid tissues. How T cells are maintained in various tissues, and how they relate to antigen-experienced memory T cells in lymphoid organs are not fully understood. By barcode-based lineage tracing and single-cell transcriptome analysis, we found a distinct population of CD69CD103 virus-specific CD8 T cells in draining lymph nodes (dLNs) following intranasal influenza infection. Intriguingly, these dLN T cells and lung T cells shared similar function-neutral barcode contents and transcriptomic features, implicating local circulation between the lung and dLNs in the maintenance of resident memory. Ablation of CXCR3 from CD8 T cells, which impairs lung T generation, severely reduced the abundance of dLN T cells, suggesting that dLN T cells are connected to lung T cells by retrograde migration. Our screen for chemokines and chemokine receptors implicated the CCR5-CCL5 axis in promoting lung-to-dLN migration. Temporary CCR5 blockade by intratracheal administration of Maraviroc, a CCR5 inhibitor, reduced the abundance of dLN T cells without affecting lung T cells. By intratracheal cell transfer, CCR5-deficient CD8 T cells were found impaired in lung-to-dLN migration. Finally, dLN T cells actively participated in the secondary response and could reconstitute lung T cells following influenza infection. Our results support a model in which lung-to-dLN TRM retrograde migration helps maintain the CD8 memory resident in the respiratory tract and optimizes the local T-cell response to reinfection.
组织驻留记忆T细胞（T细胞）在抵御病原体侵入屏障部位和其他非淋巴组织中发挥关键作用。T细胞如何在各种组织中维持，以及它们与淋巴器官中经历过抗原的记忆T细胞有何关系，目前尚不完全清楚。通过基于条形码的谱系追踪和单细胞转录组分析，我们发现鼻内感染流感后引流淋巴结（dLNs）中存在一群独特的CD69CD103病毒特异性CD8 T细胞。有趣的是，这些dLN T细胞和肺T细胞具有相似的功能中性条形码内容和转录组特征，这表明肺和dLNs之间的局部循环在维持驻留记忆中发挥作用。从CD8 T细胞中剔除CXCR3会损害肺T细胞的生成，并严重降低dLN T细胞的丰度，这表明dLN T细胞通过逆行迁移与肺T细胞相连。我们对趋化因子和趋化因子受体的筛选表明CCR5-CCL5轴在促进肺到dLN的迁移中起作用。通过气管内给予CCR5抑制剂马拉维若进行临时CCR5阻断，可降低dLN T细胞的丰度，而不影响肺T细胞。通过气管内细胞转移发现，缺乏CCR5的CD8 T细胞在肺到dLN的迁移中受损。最后，dLN T细胞积极参与二次反应，并在流感感染后可重建肺T细胞。我们的结果支持一种模型，即肺到dLN的TRM逆行迁移有助于维持呼吸道中的CD8记忆，并优化局部T细胞对再感染的反应。
