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human CD8<sup>+</sup> T cell clone 6C5 has previously been shown to recognize the <i>tert</i>-butyl-modified Bax<sub>161-170</sub> peptide LLSY(3-<i>t</i>Bu)FGTPT presented by HLA-A*02:01. This nonnatural epitope was likely created as a by-product of fluorenylmethoxycarbonyl protecting group peptide synthesis and bound poorly to HLA-A*02:01. In this study, we used a systematic approach to identify and characterize natural ligands for the 6C5 TCR. Functional analyses revealed that 6C5 T cells only recognized the LLSYFGTPT peptide when <i>t</i>Bu was added to the tyrosine residue and did not recognize the LLSYFGTPT peptide modified with larger (di-<i>t</i>Bu) or smaller chemical groups (Me). Combinatorial peptide library screening further showed that 6C5 T cells recognized a series of self-derived peptides with dissimilar amino acid sequences to LLSY(3-<i>t</i>Bu)FGTPT. Structural studies of LLSY(3-<i>t</i>Bu)FGTPT and two other activating nonamers (IIGWMWIPV and LLGWVFAQV) in complex with HLA-A*02:01 demonstrated similar overall peptide conformations and highlighted the importance of the position (P) 4 residue for T cell recognition, particularly the capacity of the bulky amino acid tryptophan to substitute for the <i>t</i>Bu-modified tyrosine residue in conjunction with other changes at P5 and P6. Collectively, these results indicated that chemical modifications directly altered the immunogenicity of a synthetic peptide via molecular mimicry, leading to the inadvertent activation of a T cell clone with unexpected and potentially autoreactive specificities.","bibjson":{"author":[{"initials":"S","lastname":"Man","name":"Man S"},{"initials":"JE","lastname":"Redman","name":"Redman JE"},{"initials":"DL","lastname":"Cross","name":"Cross DL"},{"initials":"DK","lastname":"Cole","name":"Cole DK"},{"initials":"I","lastname":"Can","name":"Can I"},{"initials":"B","lastname":"Davies","name":"Davies B"},{"initials":"SS","lastname":"Hashimdeen","name":"Hashimdeen SS"},{"initials":"R","lastname":"Reid","name":"Reid R"},{"initials":"S","lastname":"Llewellyn-Lacey","name":"Llewellyn-Lacey S"},{"initials":"KL","lastname":"Miners","name":"Miners KL"},{"initials":"K","lastname":"Ladell","name":"Ladell K"},{"initials":"A","lastname":"Lissina","name":"Lissina A"},{"initials":"PE","lastname":"Brown","name":"Brown PE"},{"initials":"L","lastname":"Wooldridge","name":"Wooldridge L"},{"initials":"DA","lastname":"Price","name":"Price DA"},{"initials":"PJ","lastname":"Rizkallah","name":"Rizkallah PJ"}],"identifier":[{"id":"10.4049/jimmunol.2000756","type":"doi"},{"id":"34321228","type":"pubmed"}],"issue":["4"],"journal":{"iso_abbreviation":"J Immunol","name":""},"pages":["1009-1017"],"title":"Synthetic Peptides with Inadvertent Chemical Modifications Can Activate Potentially Autoreactive T Cells.","type":"article","url":"http://www.jimmunol.org/lookup/doi/10.4049/jimmunol.2000756","volume":["207"],"year":[2021]},"in_pmc":"N","in_pmce":"N","open_access":"N"},"resolution":"2.68","same_as":{"pdbe":{"url":"https://www.ebi.ac.uk/pdbe/entry/pdb/6z9x"},"rcsb":{"url":"https://www.rcsb.org/structure/6z9x"}},"species":{"common_name":"Human","match_type":"histo:assign_species","scientific_name":"Homo sapiens","slug":"homo_sapiens"},"tcr":null,"title":"HLA-A*02:01 binding \"LLSXFGTPT\" at 2.68&#8491; resolution","unique_chain_count":3}}