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leukocyte antigen (HLA) class I molecules generally present peptides (p) of 8 to 11 amino acids (aa) in length. Although an increasing number of examples with lengthy (>11 aa) peptides, presented mostly by HLA-B alleles, have been reported. Here we characterize HLA-A*02:01 restricted, in addition to the HLA-B*0702 and HLA-B*4402 restricted, lengthy peptides (>11 aa) arising from the B-cell ligandome. We analyzed a number of 15-mer peptides presented by HLA-A*02:01, and confirmed pHLA-I formation by HLA folding and thermal stability assays. Surprisingly the binding affinity and stability of the 15-mer epitopes in complex with HLA-A*02:01 were comparable with the values observed for canonical length (8 to 11 aa) HLA-A*02:01-restricted peptides. We solved the structures of two 15-mer epitopes in complex with HLA-A*02:01, within which the peptides adopted distinct super-bulged conformations. Moreover, we demonstrate that T-cells can recognize the 15-mer peptides in the context of HLA-A*02:01, indicating that these 15-mer peptides represent immunogenic ligands. Collectively, our data expand our understanding of longer epitopes in the context of HLA-I, highlighting that they are not limited to the HLA-B family, but can bind the ubiquitous HLA-A*02:01 molecule, and play an important role in T-cell immunity.","bibjson":{"author":[{"initials":"C","lastname":"Hassan","name":"Hassan C"},{"initials":"E","lastname":"Chabrol","name":"Chabrol E"},{"initials":"L","lastname":"Jahn","name":"Jahn L"},{"initials":"MG","lastname":"Kester","name":"Kester MG"},{"initials":"AH","lastname":"de Ru","name":"de Ru AH"},{"initials":"JW","lastname":"Drijfhout","name":"Drijfhout JW"},{"initials":"J","lastname":"Rossjohn","name":"Rossjohn J"},{"initials":"JH","lastname":"Falkenburg","name":"Falkenburg JH"},{"initials":"MH","lastname":"Heemskerk","name":"Heemskerk MH"},{"initials":"S","lastname":"Gras","name":"Gras S"},{"initials":"PA","lastname":"van Veelen","name":"van Veelen PA"}],"identifier":[{"id":"10.1074/jbc.M114.607028","type":"doi"},{"id":"25505266","type":"pubmed"}],"issue":[null],"journal":{"iso_abbreviation":"J. 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