Factors Contributing to Immunogenicity and pMHC Complex Binding Affinity

Not every potential antigenic peptide is processed and presented by MHC molecules on the cell surface, and not all MHC-presented peptides become immunogenic T-cell epitopes.

Immunogenicity depends on several factors, including protein expression, antigen processing and transport, pMHC binding affinity and pMHC complex stability, altered peptide sequences, competitive exclusion, and recognition of the complex by a T-cell receptor¹.

The binding affinity of a peptide to an MHC molecule is influenced by multiple factors, including:

1. Peptide sequence: The primary sequence of amino acids in a peptide determines its overall shape, charge, and hydrophobicity, directly impacting its binding affinity to the MHC molecule. Specific sequences may interact more favorably with the MHC binding groove.

2. Modified peptide sequence²: Post-translational modifications, such as phosphorylation, glycosylation or methylation, can either enhance or reduce the binding by altering the chemical properties of the peptide influencing the interaction with the MHC binding pocket.

3. Peptide length: Optimal length of the peptide is crucial for fitting into the MHC binding groove, ensuring stable binding and proper presentation. MHC class I molecules bind peptides of 8-10 amino acids, while MHC class II molecules usually accommodate 13-17 amino acids though shorter or longer lengths are not uncommon.

4. Anchor residues^3,4: Specific positions within the peptide interact directly with the MHC binding groove, critically determining binding strength.

5. Peptide secondary structure^4,5: The conformation of the peptide, such as alpha-helices or beta-sheets, affects how well the peptide fits into the MHC binding groove. Peptides that can adopt conformations compatible with the binding groove are more likely to bind with higher affinity.

6. HLA isotype and binding cleft⁶: Different HLA (human leukocyte antigen) isotypes have unique binding grooves, influencing which peptide can bind effectively, based on the shape, depth, and chemical environment of the MHC binding cleft. Specific HLA alleles have unique binding preferences, affecting the peptide repertoire presented to T cells.

Identifying the correct epitopes is crucial to understanding cellular immune responses, and determining which peptides are presented by MHC molecules has made significant progress in recent years.

pMHC binding prediction tools play an important role in identifying epitope candidates, using data on binding affinity, peptide processing and immunogenicity. By refining these predictions, the accuracy of epitope identification continues to improve, playing a key role in the development of vaccines and immunotherapies. Learn more about the tools available to predict peptide-MHC binding affinity and how to validate pMHC binding 

References

1. Calis JJ, Maybeno M, Greenbaum JA, Weiskopf D, De Silva AD, Sette A, Keşmir C, Peters B. Properties of MHC class I presented peptides that enhance immunogenicity. PLoS Comput Biol. 2013. DOI: 10.1371/journal.pcbi.1003266
2. Tanaka Y, Amos KD, Joo HG, Eberlein TJ, Goedegebuure PS. Modification of the HER2/NEU-derived tumor antigen GP2 improves induction of GP2-reactive cytotoxic T lymphocytes. Int J Cancer. 2001. DOI: 10.1002/ijc.1508

3. Harndahl M, Rasmussen M, Roder G, Dalgaard Pedersen I, Sørensen M, Nielsen M, Buus S. Peptide-MHC class I stability is a better predictor than peptide affinity of CTL immunogenicity. Eur J Immunol. 2012. DOI: 1002/eji.201141774

4. Doytchinova IA, Walshe VA, Jones NA, Gloster SE, Borrow P, Flower DR. Coupling in silico and in vitro analysis of peptide-MHC binding: a bioinformatic approach enabling prediction of superbinding peptides and anchorless epitopes. J Immunol. 2004. DOI: 4049/jimmunol.172.12.7495

5. Kuhns JJ, Batalia MA, Yan S, Collins EJ. Poor binding of a HER-2/neu epitope (GP2) to HLA-A2.1 is due to a lack of interactions with the center of the peptide. J Biol Chem. 1999. DOI: 1074/jbc.274.51.36422

6. Zhang, YH., Xing, Z., Liu, C. et al. Identification of the core regulators of the HLA I-peptide binding process. Sci Rep 7, 42768 (2017). https://doi.org/10.1038/srep42768

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