Synthetic Peptides with Inadvertent Chemical Modifications Can Activate Potentially Autoreactive T Cells.

Area of Science:

• Immunology
• Molecular Biology
• Structural Biology

Background:

• The human CD8+ T cell clone 6C5 recognizes a synthetic peptide, LLSY(3-tBu)FGTPT, presented by HLA-A*02:01.
• This nonnatural epitope likely arose during peptide synthesis and exhibited poor binding to HLA-A*02:01.

Purpose of the Study:

• To identify and characterize natural ligands for the 6C5 T cell receptor (TCR).
• To understand the structural basis of T cell recognition and the role of chemical modifications in peptide immunogenicity.

Main Methods:

• Functional assays to assess T cell recognition of modified peptides.
• Combinatorial peptide library screening to identify natural ligands.
• Structural studies of peptide-MHC complexes using X-ray crystallography.

Main Results:

• 6C5 T cells specifically recognized LLSYFGTPT only when modified with tert-butyl (tBu) on the tyrosine residue.
• Screening identified natural peptides with dissimilar sequences that activated 6C5 T cells.
• Structural analysis revealed the importance of the P4 residue, with tryptophan mimicking the tBu-modified tyrosine.

Conclusions:

• Chemical modifications on synthetic peptides can alter immunogenicity through molecular mimicry.
• This process can lead to inadvertent T cell activation with potentially autoreactive specificities.
• The findings highlight the importance of considering synthetic by-products in T cell epitope discovery.