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

Virus-specific nasal resident T cells are important for protection against subsequent infection with a similar virus. Here we examine 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 are obtained from participants during sinus surgery. Analysis of activation-induced markers implicates that a considerable proportion of spike (S)-reactive nasal CD8⁺ T cells express CD103, a tissue-resident marker. MHC-I multimer staining is performed to analyze the ex vivo phenotype and function of SARS-CoV-2 S-specific CD8⁺ T cells. We detect 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 remain present in nasal tissues over one year after the last exposure to S antigen, although the frequency decreases. Upon direct ex vivo stimulation with epitope peptides, nasal multimer⁺CD8⁺ T cells–particularly the CD49a⁺ subset–exhibit immediate effector functions, including IFN-γ production. CITE-seq analysis of S-reactive AIM⁺CD8⁺ T cells confirms the enhanced effector function of 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.