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

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/M1₅₈), 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*57:01NP_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/M1₅₈ were generally immunodominant, A2/M1₅₈⁺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/M1₅₈⁺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/M1₅₈⁺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.