Ma, H.-T. | bioRxiv Science

bioRxiv2026

Neural Arming Niche in Tumor-Draining Lymph Nodes Programs CD8⁺T Cell Cytotoxicity via GZMB Norepinephrinylation

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.

cancer biology↗

bioRxiv2022

The tau oligomer antibody APNmAb005 detects early-stage pathological tau enriched at synapses and rescues neuronal loss in long-term treatments

Numerous tau immunotherapies are being developed against Alzheimers disease (AD), but it has been challenging to specifically target early-stage tau aggregates using conformation-dependent antibodies. Here, we report a monoclonal antibody, APNmAb005, that recognized a conformational epitope associated with tau oligomers. In AD brain extracts, mAb005 preferentially recognized oligomeric tau in the synapse over monomeric tau in the cytosol. In the prefrontal cortex and hippocampus, mAb005 immunoreactivity was strongly present in early-stage AD but surprisingly diminished in late-stage AD (Braak stage VI). mAb005 also recognized aggregates in 3R tauopathies (Picks disease) and 4R tauopathies (corticobasal degeneration and progressive supranuclear palsy), including those in astrocytes and oligodendrocytes. In rTg4510 mice (P301L tau), mAb005 immunoreactivity first appeared in distal neurites but much later in neuronal somas. Thus, the mAb005 epitope appears to be associated with early-stage oligomers of tau (esoTau) that accumulate around synapses in AD, which is also detectable in both 3R and 4R tauopathies. In cellular uptake models of tauopathy transmission, mAb005 blocked the formation of intracellular inclusions induced by incubation with rTg4510 mouse brain extracts. Long-term treatments with mAb005 in rTg4510 mice partially rescued synaptic and neuronal loss in the hippocampus without promoting overall tau clearance. Our data suggest that immunotherapies targeting esoTau enriched around synaptic sites may alleviate tau toxicity against synapses and neurons, which may be a promising treatment strategy against AD. One Sentence SummaryA tau-conformer antibody recognizing synaptic oligomers and 3R, 4R, and mixed aggregates in humans rescues neuronal loss in mouse tauopathy models.

neuroscience↗