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Seasonal influenza virus infections cause 290,000–650,000 deaths annually and severe morbidity in 3–5 million people. CD8 +  T-cell responses towards virus-derived peptide/human leukocyte antigen (HLA) complexes provide the broadest cross-reactive immunity against human influenza viruses. Several universally-conserved CD8 +  T-cell specificities that elicit prominent responses against human influenza A viruses (IAVs) have been identified. These include HLA-A*02:01-M1 58-66  (A2/M1 58 ), HLA-A*03:01-NP 265-273 , HLA-B*08:01-NP 225-233 , HLA-B*18:01-NP 219-226 , HLA-B*27:05-NP 383-391  and HLA-B*57:01-NP 199-207 . The immunodominance hierarchies across these universal CD8 +  T-cell epitopes were however unknown. Here, we probed immunodominance status of influenza-specific universal CD8 +  T-cells in HLA-I heterozygote individuals expressing two or more universal HLAs for IAV. We found that while CD8 +  T-cell responses directed towards A2/M1 58  were generally immunodominant, A2/M1 58  + CD8 +  T-cells were markedly diminished (subdominant) in HLA-A*02:01/B*27:05-expressing donors following  ex vivo  and  in vitro  analyses. A2/M1 58  + CD8 +  T-cells in non-HLA-B*27:05 individuals were immunodominant, contained optimal public TRBV19/TRAV27 TCRαβ clonotypes and displayed highly polyfunctional and proliferative capacity, while A2/M1 58  + CD8 +  T cells in HLA-B*27:05-expressing donors were subdominant, with largely distinct TCRαβ clonotypes and consequently markedly reduced avidity, proliferative and polyfunctional efficacy. Our data illustrate altered immunodominance patterns and immunodomination within human influenza-specific CD8 +  T-cells. Accordingly, our work highlights the importance of understanding immunodominance hierarchies within individual donors across a spectrum of prominent virus-specific CD8 +  T-cell specificities prior to designing T cell-directed vaccines and immunotherapies, for influenza and other infectious diseases.

HLA-B*27:05 alters immunodominance hierarchy of universal influenza-specific CD8+ T cells