SARS-CoV-2 spike-specific nasal-resident CD49a+CD8+ memory T cells exert immediate effector functions with enhanced IFN-g production

Here we examined the phenotypes and functions of SARS-CoV-2-specific T cells in the nasal mucosa of vaccinated individuals with breakthrough infection (BTI) or without infection. Nasal tissues were obtained from participants during sinus surgery. Analysis of activation-induced markers revealed spike (S)-reactive nasal T cells expressing tissue-resident markers, including CD103. MHC-I multimer staining was performed to analyze the ex vivo phenotype and function of SARS-CoV-2 S-specific CD8⁺ T cells. We detected multimer⁺CD8⁺ T cells with tissue-resident phenotypes in nasal tissue samples from vaccinees without infection as well as vaccinees with BTI. Multimer⁺CD8⁺ T cells remained present in nasal tissues over one year after the last exposure to S antigen, although the frequency decreased. Upon direct ex vivo stimulation with epitope peptides, nasal multimer⁺CD8⁺ T cells – particularly the CD49a⁺ subset – exhibited immediate effector functions, including IFN-g production. CITE-seq analysis of S-reactive AIM⁺CD8⁺ T cells confirmed enhanced IFN-g expression in the CD49a⁺ subset. These findings indicate that among individuals previously exposed to S antigen by vaccination or BTI, S-specific nasal-resident CD49a⁺CD8⁺ memory T cells can rapidly respond to SARS-CoV-2 during infection or reinfection.