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influenza viruses lead to severe illness in high-risk populations, host genetic factors associated with severe disease are largely unknown. As the HLA-A*68:01 allele can be linked to severe pandemic 2009-H1N1 disease, we investigate a potential impairment of HLA-A*68:01-restricted CD8<sup>+</sup> T cells to mount robust responses. We elucidate the HLA-A*68:01<sup>+</sup>CD8<sup>+</sup> T\u00a0cell response directed toward an extended influenza-derived nucleoprotein (NP) peptide and show that only ~35% individuals have immunodominant A68/NP<sub>145</sub><sup>+</sup>CD8<sup>+</sup> T\u00a0cell responses. Dissecting A68/NP<sub>145</sub><sup>+</sup>CD8<sup>+</sup> T cells in low vs. medium/high responders reveals that high responding donors have A68/NP<sub>145</sub><sup>+</sup>CD8<sup>+</sup> memory T cells with clonally expanded TCR\u03b1\u03b2s, while low-responders display A68/NP<sub>145</sub><sup>+</sup>CD8<sup>+</sup> T cells with predominantly na\u00efve phenotypes and non-expanded TCR\u03b1\u03b2s. Single-cell index sorting and TCR\u03b1\u03b2 analyses link expansion of A68/NP<sub>145</sub><sup>+</sup>CD8<sup>+</sup> T cells to their memory potential. Our study demonstrates the immunodominance potential of influenza-specific CD8<sup>+</sup> T cells presented by a risk HLA-A*68:01 molecule and advocates for priming CD8<sup>+</sup> T\u00a0cell compartments in HLA-A*68:01-expressing individuals for establishment of pre-existing protective memory T\u00a0cell pools.","bibjson":{"author":[{"initials":"CE","lastname":"van de Sandt","name":"van de Sandt CE"},{"initials":"EB","lastname":"Clemens","name":"Clemens EB"},{"initials":"EJ","lastname":"Grant","name":"Grant EJ"},{"initials":"LC","lastname":"Rowntree","name":"Rowntree LC"},{"initials":"S","lastname":"Sant","name":"Sant S"},{"initials":"H","lastname":"Halim","name":"Halim H"},{"initials":"J","lastname":"Crowe","name":"Crowe J"},{"initials":"AC","lastname":"Cheng","name":"Cheng AC"},{"initials":"TC","lastname":"Kotsimbos","name":"Kotsimbos TC"},{"initials":"M","lastname":"Richards","name":"Richards M"},{"initials":"A","lastname":"Miller","name":"Miller A"},{"initials":"SYC","lastname":"Tong","name":"Tong SYC"},{"initials":"J","lastname":"Rossjohn","name":"Rossjohn J"},{"initials":"THO","lastname":"Nguyen","name":"Nguyen THO"},{"initials":"S","lastname":"Gras","name":"Gras S"},{"initials":"W","lastname":"Chen","name":"Chen W"},{"initials":"K","lastname":"Kedzierska","name":"Kedzierska K"}],"identifier":[{"id":"10.1038/s41467-019-13346-4","type":"doi"},{"id":"31811120","type":"pubmed"}],"issue":["1"],"journal":{"iso_abbreviation":"Nat Commun","name":""},"pages":["5579"],"title":"Challenging immunodominance of influenza-specific CD8<sub>+</sub> T cell responses restricted by the risk-associated HLA-A*68:01 allomorph.","type":"article","url":"http://www.nature.com/articles/s41467-019-13346-4","volume":["10"],"year":[2019]},"in_pmc":"N","in_pmce":"Y","open_access":"Y"},"resolution":"1.89","same_as":{"pdbe":{"url":"https://www.ebi.ac.uk/pdbe/entry/pdb/6pbh"},"rcsb":{"url":"https://www.rcsb.org/structure/6pbh"}},"species":{"common_name":"Human","match_type":"histo:assign_species","scientific_name":"Homo sapiens","slug":"homo_sapiens"},"tcr":null,"title":"HLA-A*68:01 binding \"DATYQRTRALVR\" at 1.89&#8491; resolution","unique_chain_count":3}}