Sympathetic-Epithelial Crosstalk Governs Regionalized CD8+ TRM Cell Immunosurveillance in the Skin

Epithelial cells, immune cells, and nerves converge at barrier tissues to collaboratively defend against pathogens and malignancies, but the mechanisms mediating their coordination remain poorly understood. Here we show that in the skin, sympathetic nerves interact with epidermal stem cells (EpiSCs) to regulate CD8+ tissue-resident memory T (TRM) cell density, thereby modulating local immunosurveillance against developing melanoma. Sympathetic nerves anchor on skin epithelium and establish synapse-like connections with EpiSCs, modulating their secretion of chemokine ligand CXCL16 via norepinephrine-ADRB2 signaling. Reduced sympathetic tone elevates CXCL16 secretion, increasing CD8+ TRM cell abundance in the skin epithelium and enhancing local cancer immunosurveillance. Conversely, heightened sympathetic activity during acute stress decreases CD8+ TRM cell number, allowing nascent cancer cells to evade elimination and propagate. Our study unveils a neuro-epithelial-immune axis that governs CD8+ TRM cell dynamics at barrier tissues, and illustrates how regional immunosurveillance can be influenced by systemic neuronal inputs and mental status. Overall design: To investigate what molecule was responsible for the recruitment of CD8+ T cells in skin epidermis, we treated the Gi-DREADD and control mice with CNO to suppress the activity of sympathetic neuron. EpiSCs were then isolated fluorescence-activated cell sorting (FACS)

上皮细胞、免疫细胞与神经在屏障组织中汇聚，协同抵御病原体与恶性肿瘤，但介导三者间协调互作的分子机制仍有待阐明。本研究针对皮肤组织展开研究，发现交感神经可与表皮干细胞（Epidermal Stem Cells, EpiSCs）相互作用，调节CD8+组织驻留记忆T（Tissue-resident memory T, TRM）细胞的密度，进而调控针对进展性黑色素瘤的局部免疫监视功能。交感神经锚定皮肤上皮，并与表皮干细胞形成突触样连接，通过去甲肾上腺素-ADRB2信号通路调节其分泌趋化因子配体CXCL16。交感张力降低会上调CXCL16的分泌，增加皮肤上皮中CD8+ TRM细胞的丰度，增强局部肿瘤免疫监视；反之，急性应激期间交感活动增强则会减少CD8+ TRM细胞的数量，使新生肿瘤细胞得以逃避免疫清除并增殖扩散。本研究揭示了一条调控屏障组织中CD8+ TRM细胞动态平衡的神经-上皮-免疫轴，并阐明了全身神经元信号与精神状态可对局部免疫监视产生影响。

实验设计：为探究皮肤表皮中招募CD8+ T细胞的关键分子，我们使用CNO处理Gi-DREADD转基因小鼠及对照小鼠，以抑制交感神经元的活性，随后通过荧光激活细胞分选（Fluorescence-Activated Cell Sorting, FACS）分离表皮干细胞。