Sympathetic-epithelial crosstalk governs tissue-resident memory T cell immunosurveillance in the skin
Summary
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 (TRM) cells, thereby influencing regional cancer immunosurveillance. Sympathetic nerves do not communicate directly with CD8+ TRM cells. Instead, they form synapse-like structures near basal keratinocytes and dynamically modu
Content
# Sympathetic-epithelial crosstalk governs tissue-resident memory T cell immunosurveillance in the skin
*Published: 2026 Mar 5*
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 (TRM) cells, thereby influencing
regional cancer immunosurveillance. Sympathetic nerves do not communicate
directly with CD8+ TRM cells. Instead, they form synapse-like structures near
basal keratinocytes and dynamically modulate epithelial-derived signals
essential for skin CD8+ TRM formation via norepinephrine-ADRB2 signaling.
Reduced sympathetic tone elevates epithelial-derived signals to promote CD8+ TRM
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+ TRM abundance in the skin, enabling
rapid adjustment of immunosurveillance strength at the barrier interface by
inputs from the sympathetic nervous system.
DOI: 10.1016/j.cell.2025.12.043