Non-Enzymatic Structural Modifications Reshape Peptide Presentation and Antigen Recognition.

Area of Science:

• Immunology
• Biochemistry
• Proteomics

Background:

• Adaptive immunity relies on Major Histocompatibility Complex class I (MHC-I) presenting antigenic peptides to cytotoxic T-cells.
• Peptide selection for MHC-I presentation normally ensures self-tolerance, but chemical modifications can interfere.
• Post-translational modifications (PTMs) and non-enzymatic changes alter peptide structure, potentially affecting immune recognition.

Purpose of the Study:

• To investigate the impact of non-enzymatic PTMs on antigen presentation and T cell recognition.
• To understand how these modifications affect the cancer-associated immunopeptidome.

Main Methods:

• Synthesis of peptide variants with common non-enzymatic PTMs using the SIINFEKL model epitope.
• Assessment of modified peptides' effects on MHC-I binding affinity and T cell recognition.
• Development of an alkyne-modified probe for enrichment and identification of non-enzymatically acylated peptides.

Main Results:

• Non-enzymatic PTMs significantly alter peptide affinity for MHC-I molecules.
• These modifications were shown to impact the cancer-associated immunopeptidome.
• A novel method was established to identify sites of non-enzymatic acylation relevant to MHC-I display.

Conclusions:

• Non-enzymatic PTMs are critical modulators of the immunopeptidome.
• These modifications play a significant role in shaping adaptive immune responses.
• Understanding these chemical alterations is crucial for cancer immunology and immunotherapy.