Long-distance communication between CD8 T cells and brainstem neurons determines sickness behaviors and infection outcome 2254620

Abstract Introduction CD8 T cells are classically known for their cytotoxic role in eliminating infected, cancerous, and damaged cells. However, their potential for non-cytotoxic, long-distance, and bidirectional communication with neurons has remained unexplored. Methods Mice were intravenously infected with lymphocytic choriomeningitis virus Clone 13, as a natural model of a sustained viral infection. We combined behavioral assays, immunohistochemistry, pharmacological blockade, stereotactic ablation of specific brain neurons, flow cytometry, and single-cell RNA sequencing to dissect how CD8 T cells and neurons bidirectionally communicate during viral infection. Results Depletion of CD8 T cells abolished sickness behaviors observed one week after a systemic viral infection, while adoptive transfer of CD8 T cells into T cell and B cell-deficient mice restored these behaviors. Blocking CD8 T cell brain entry did not affect behaviors. Whole-brain c-Fos mapping revealed CD8 T cell-dependent activation of caudal nucleus of solitary tract (cNTS), including dopamine β-hydroxylase—positive (DBH+) neurons, at the peak of sickness behaviors. Ablation of these neurons attenuated sickness behaviors and enhanced effector-like CD8 T-cell responses in spleen, lung, and blood. Single-cell RNA sequencing uncovered an unconventional CD8 T cell subset co-expressing TCR-α, β, and γ chains, and enriched for IL-2 signature and cytotoxic genes following the neuronal ablation. Although viral loads decreased, the neuronal ablation caused severe, CD8 T cell-dependent, lung hemorrhage and increased mortality. Conclusion Our findings reveal a previously unrecognized systemic feedback loop wherein CD8 T cells remotely activate cNTS DBH+ neurons without entering the brain. These neurons not only drive sickness behaviors but also restrain CD8 T cell effector functions to prevent fatal immunopathology, at the expense of viral control. This immune—neural axis integrates host behavior and antiviral immunity into a single regulatory circuit. Funding Source n/a Topic Categories Neuroimmunology (NEUR)