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CD8 T cell response to viral infections involves recognition of 8-10-mer peptides presented by MHC-I molecules. However, proteasomes generate predominantly 2-7-mer peptides, but the role of these peptides is largely unknown. Here, we show that single short peptides of <8-mer from Latent Membrane Protein 2 (LMP2) of Epstein Barr Virus (EBV) can bind HLA-A*11:01 and stimulate CD8<sup>+</sup> cells. Surprisingly, two peptide fragments between 4-7-mer derived from LMP2<sub>(340-349)</sub> were able to complement each other, forming combination epitopes that can stimulate specific CD8<sup>+</sup> T cell responses. Moreover, peptides from self-antigens can complement non-self peptides within the HLA binding cleft, forming neoepitopes. Solved structures of a tetra-complex comprising two peptides, HLA and \u03b22-microglobulin revealed the free terminals of the two peptides to adopt an upward conformation directed towards the T cell receptor. Our results demonstrate a previously unknown mix-and-match combination of dual peptide occupancy in HLA that can generate vast combinatorial complexity.","bibjson":{"author":[{"initials":"Z","lastname":"Xiao","name":"Xiao Z"},{"initials":"Z","lastname":"Ye","name":"Ye Z"},{"initials":"VS","lastname":"Tadwal","name":"Tadwal VS"},{"initials":"M","lastname":"Shen","name":"Shen M"},{"initials":"EC","lastname":"Ren","name":"Ren EC"}],"identifier":[{"id":"10.1038/s41598-017-05171-w","type":"doi"},{"id":"28698575","type":"pubmed"}],"issue":["1"],"journal":{"iso_abbreviation":"Sci Rep","name":""},"pages":["5072"],"title":"Dual non-contiguous peptide occupancy of HLA class I evoke antiviral human CD8 T cell response and form neo-epitopes with self-antigens.","type":"article","url":"http://www.nature.com/articles/s41598-017-05171-w","volume":["7"],"year":[2017]},"in_pmc":"N","in_pmce":"Y","open_access":"Y"},"resolution":"1.94","same_as":{"pdbe":{"url":"https://www.ebi.ac.uk/pdbe/entry/pdb/5grg"},"rcsb":{"url":"https://www.rcsb.org/structure/5grg"}},"species":{"common_name":"Human","match_type":"histo:assign_species","scientific_name":"Homo sapiens","slug":"homo_sapiens"},"tcr":null,"title":"HLA-A*11:01 binding peptide fragments at 1.94&#8491; resolution","unique_chain_count":4}}