Sympathetic Nerves Regulate Immunosurveillance in the Skin

Skin-resident memory CD8+ T (TRM) cells are central to immune defense in barrier tissues. Located in the skin epithelium, CD8+ TRM cells provide rapid protection by releasing inflammatory signals and recruiting other immune cells. Higher TRM cell density is associated with stronger local immune response and better outcomes in melanoma, yet how TRM cell numbers are dynamically regulated to adjust immune surveillance remains unclear. Given the close interaction between sympathetic nerves and immune cells at barrier tissues, Zhang, Miao, and colleagues investigated whether neuronal signaling shapes TRM cell abundance in the skin. Their results showed that cutaneous sympathetic nerves indirectly restrain CD8+ TRM cell recruitment. Chemical or genetic ablation of cutaneous sympathetic nerves led to a marked increase in TRM cell number. Pharmacologic blockade of β-adrenergic receptors with nadolol produced a similar effect, indicating that norepinephrine (NE) signaling limits TRM cell density. Single-cell RNA sequencing analysis identified epidermal keratinocytes as the primary NE-responsive cells, as these cells expressed high levels of the β2-arenergic receptor (Adrb2). Accordingly, keratinocyte-specific deletion of Adrb2 phenocopied sympathetic inhibition and increased TRM cell number. Adoptive transfer experiments with labeled activated CD8+ T cells showed that sympathetic inhibition enhanced T cell homing to the skin, where these cells acquired a TRM signature and formed a durably larger pool of resident cells. Mechanistically, RNA sequencing and immunostaining analyses revealed increased expression of the chemokine CXCL16 in keratinocytes. Blocking CXCL16 or deleting it specifically in keratinocytes prevented CD8+ T cell homing and the rise in CD8+ TRM cells, demonstrating that CXCL16 is required for enhanced T cell recruitment and TRM abundance. Functionally, inhibiting sympathetic signaling improved tumor control in a mouse model of melanoma in a CXCL16-dependent manner. Conversely, neuronal activation, NE supplementation, or Cxcl16 depletion rapidly reduced TRM cell numbers. Together, these findings define a novel neuro–epithelial–immune axis in which sympathetic nerves tune epithelial chemokine production to control TRM cell density, with implications for cancer immunotherapy, vaccination, and autoimmune disease.Zhang P, Miao J, Yu H, Yu H, Liu C, Zhao L, et al. Sympathetic-epithelial crosstalk governs tissue-resident memory T cell immunosurveillance in the skin. Cell 2026 Jan 29 [Epub ahead of print].Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.