Antiviral CD8⁺ T cells Engage a Neuroimmune Circuit to Drive Anorexia

Abstract Infection-induced anorexia is a conserved sickness response that contributes to host defense and tolerance1-3. Although innate immune mediators are known to induce anorexia through neuro-immune communication 1,4, whether and how adaptive immunity engages neural circuits to regulate feeding remains poorly understood. Here, we identify a neuro-immune pathway linking antigen-specific antiviral CD8⁺ T-cell responses to brainstem control of feeding during lymphocytic choriomeningitis virus (LCMV) infection. Antigen-specific CD8⁺ T cells were required for late-phase anorexia and neuronal activation in the nucleus of the solitary tract (NTS), where Vglut2⁺ excitatory neurons mediated feeding suppression. Mechanistically, CD8⁺ T cell-intrinsic ST2-MyD88 signaling promoted cytotoxic effector function and peripheral sympathetic nerve injury, while vagal afferent signaling conveyed peripheral neural perturbations to the brainstem. Chemical sympathetic denervation was sufficient to trigger NTS activation and anorexia, whereas sympathetic denervation before infection or disruption of the CD8⁺ T-cell effector program attenuated these responses. Together, our findings reveal that IL-33-ST2-MyD88 signaling programs antiviral CD8⁺ T-cell effector function to engage a peripheral sympathetic-vagal-brainstem axis that suppresses feeding. This work uncovers a neuro-immune mechanism by which adaptive antiviral immunity extends beyond pathogen control to orchestrate infection-associated behavioral adaptation.