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Publication Abstract from PubMed

The human CD8(+) T cell clone 6C5 has previously been shown to recognize the tert-butyl-modified Bax(161-170) peptide LLSY(3-tBu)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 tBu was added to the tyrosine residue and did not recognize the LLSYFGTPT peptide modified with larger (di-tBu) 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-tBu)FGTPT. Structural studies of LLSY(3-tBu)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 tBu-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.

Synthetic Peptides with Inadvertent Chemical Modifications Can Activate Potentially Autoreactive T Cells.,Man S, Redman JE, Cross DL, Cole DK, Can I, Davies B, Hashimdeen SS, Reid R, Llewellyn-Lacey S, Miners KL, Ladell K, Lissina A, Brown PE, Wooldridge L, Price DA, Rizkallah PJ J Immunol. 2021 Aug 15;207(4):1009-1017. doi: 10.4049/jimmunol.2000756. Epub 2021 , Jul 28. PMID:34321228^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.