Abstract
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-M158-66 (A2/M158), HLA-A*03:01-NP265-273, HLA-B*08:01-NP225-233, HLA-B*18:01-NP219-226, HLA-B*27:05-NP383-391 and HLA-B*57:01-NP199-207. 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.
Highlights
Seasonal influenza virus infections cause 290,000–650,000 deaths annually and severe morbidity in 3–5 million people [1]
To define the immunodominance hierarchy across universal influenza CD8+ T cell epitopes (HLA-A 02:01-M158-66, human leukocyte antigen (HLA)-A 03:01-NP265-273, HLA-B 27:05-NP383-391, HLA-B 57:01NP199-207, HLA-B 18:01-NP219-226 and HLA-B 08:01-NP225-233) [5] within an individual, influenza A viruses (IAVs)-specific CD8+ T cell responses towards those epitopes were measured in healthy blood donors following peptide stimulation and IFN-γ/TNF cytokine production (Fig 1A)
When we compared the magnitude of IFN-γ+CD8+ T cell responses directed at the most studied immunodominant IAV epitope A2/ M158 [5, 17] against other universal epitope responses within the same individual, our analyses revealed that A2/M158+CD8+ T cell responses were immunodominant over HLAs A3, B8 and B18, but this was strikingly not the case in donors that co-expressed B27 or B57 (Fig 1C)
Summary
Seasonal influenza virus infections cause 290,000–650,000 deaths annually and severe morbidity in 3–5 million people [1]. Memory CD8+ T cell responses generated by seasonal IAV infection can provide broader cross-protection against subsequent challenges from distinct influenza virus strains and subtypes, called heterosubtypic immunity [4, 5, 10, 11]. Our recent studies revealed that influenza-specific CD8+ T cells can provide unprecedented immunity across all influenza A, B and C viruses capable of infecting humans [15], and across influenza A [16, 17] and influenza B viruses [15] These studies demonstrate that pre-existing CD8+ T cell immunity could reduce disease severity, decrease viral burden, ameliorate morbidity and mortality, leading to a rapid recovery of the host. Cross-strain protective CD8+ T cell-based vaccines could provide
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