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Synthetic peptides with inadvertent chemical modifications can activate potentially autoreactive T cells

Man, Stephen ORCID:, Redman, James E. ORCID:, Cross, Deborah L., Cole, David K. ORCID:, Can, Ilona, Davies, Bethan, Hashimdeen, Shaikh Shimaz, Reid, Reiss, Llewellyn-Lacey, Sian, Miners, Kelly L., Ladell, Kristin ORCID:, Lissina, Anya, Brown, Paul E., Wooldridge, Linda, Price, David A. ORCID: and Rizkallah, Pierre J. ORCID: 2021. Synthetic peptides with inadvertent chemical modifications can activate potentially autoreactive T cells. The Journal of Immunology 207 (4) , pp. 1009-1017. 10.4049/jimmunol.2000756

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The human CD8+ T cell clone 6C5 has previously been shown to recognize the tert-butyl-modified Bax161–170 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Publisher: American Association of Immunologists
ISSN: 1550-6606
Date of First Compliant Deposit: 17 September 2021
Date of Acceptance: 24 May 2021
Last Modified: 28 Mar 2024 14:30

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