Sympathetic-epithelial crosstalk governs tissue-resident memory T cell immunosurveillance in the skin

Effective host defense and immunosurveillance at barrier tissues require coordinated functions of multiple cell types. Here, we show that in the skin, sympathetic nerves engage with epidermal keratinocytes to regulate the local density of tissue-resident memory CD8⁺ T (T_RM) cells, thereby influencing regional cancer immunosurveillance. Sympathetic nerves do not communicate directly with CD8⁺ T_RM cells. Instead, they form synapse-like structures near basal keratinocytes and dynamically modulate epithelial-derived signals essential for skin CD8⁺ T_RM formation via norepinephrine-ADRB2 signaling. Reduced sympathetic tone elevates epithelial-derived signals to promote CD8⁺ T_RM development in the skin epithelium, while heightened sympathetic activity during acute stress dampens this process. Our findings unveil a neuro-epithelial-immune tri-lineage axis that calibrates local CD8⁺ T_RM abundance in the skin, enabling rapid adjustment of immunosurveillance strength at the barrier interface by inputs from the sympathetic nervous system.