Discriminating self from nonself with short peptides from large proteomes

Area of Science:

• Immunology
• Computational Biology
• Proteomics

Background:

• Peptides of nine amino acids (9-mers) are typically presented by MHC class I molecules.
• Effective self/nonself discrimination by the immune system is critical for preventing autoimmunity and responding to pathogens.
• The degree of overlap between self and foreign peptides influences immune recognition.

Purpose of the Study:

• To determine if 9-mers are unique enough for self/nonself discrimination in MHC class I presentation.
• To assess the impact of peptide length on self/nonself overlap.
• To evaluate the specificity of HLA molecules in presenting peptides.

Main Methods:

• Calculated the number of distinct 9-mers in the human proteome and various microorganisms.
• Quantified the average overlap (probability of foreign peptide occurring in self) for different peptide lengths.
• Predicted immunoproteasome cleavage, TAP translocation, and HLA-A*0201/HLA-A*0204 presentation of peptides.
• Analyzed the self/nonself overlap of exposed 7-mers after removing anchor residues from presented peptides.

Main Results:

• The average self/nonself overlap for 9-mers is approximately 0.2%, significantly lower than for 6-mers (30%) or 7-mers (3%).
• About 25% of self and nonself 9-mers are successfully processed (cleaved and translocated).
• HLA-A*0201 and HLA-A*0204 alleles show a slight preference for presenting foreign peptides over self peptides.
• Despite anchor residue binding to HLA, the exposed 7-mers retain information, showing a self/nonself overlap similar to 9-mers.

Conclusions:

• Nine amino acid peptides (9-mers) possess sufficient information for effective self/nonself discrimination in MHC class I presentation.
• HLA molecules exhibit specificity that preserves discriminatory information even after peptide binding.
• The length and processing of peptides are critical factors in immune surveillance and recognition of foreign entities.