Neural Arming Niche in Tumor-Draining Lymph Nodes Programs CD8⁺T Cell Cytotoxicity via GZMB Norepinephrinylation
Yang, Y.; Zhang, X.; Tulamaiti, A.; Xiao, S.-Y.; Qian, Y.-Z.; Luo, J.-M.; Su, G.-h.; Lu, R.; Wang, J.-J.; Ma, H.-T.; Li, X.-Q.; Shi, W.-T.; Hong, Y.-X.; Hou, J.-L.; Hu, L.; Xing, X.; Li, Q.; Li, D.-X.; Zhang, Z.
Show abstract
Lymph nodes are densely innervated neuro-immune hubs where naive T cells are primed and "armed" with cytotoxic machinery, yet how local neural cues in tumor-draining lymph nodes (tdLNs) set CD8 T cell effector reserves remains unclear. Here we show that tdLN-local sympathetic norepinephrine (NE) instructs CD8 T cell cytotoxic capacity by stabilizing the granzyme B (GZMB) pool through covalent norepinephrinylation. Exercise, used as a physiological perturbation, increases GZMB selectively in tdLN and tumor CD8 T cells without altering T cell abundance or cytokine output; tdLN sympathectomy abolishes these effects and reduces tdLN NE enrichment. Mechanistically, NE enters CD8 T cells and norepinephrinylates GZMB at Gln43, limiting UHRF1-mediated ubiquitination and proteasomal degradation. Genetic attenuation of norepinephrinylation destabilizes GZMB, impairs cytotoxicity, and accelerates tumor growth. Brief ex vivo NE conditioning increases GZMB reserves and improves adoptive tumor control.
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