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Cited by 12vaccines and immunoinformatics approachesImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

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Antigen presentation of post‐translationally modified peptides in major histocompatibility complexes

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de Wit, Alexine S, Bianchi, Frans, van den Bogaart, Geert·2025·Immunology & Cell Biology
DOI 10.1111/imcb.12839PMC PMC11792782
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Abstract

T cells of the adaptive immune system recognize pathogens and malignantly transformed cells through a process called antigen presentation. During this process, peptides are displayed on major histocompatibility complex (MHC) class I and II molecules. Self‐reactive T cells are typically removed or suppressed during T‐cell development and through peripheral tolerance mechanisms, ensuring that only T cells recognizing peptides that are either absent or present in low abundance under normal conditions remain. This selective process allows T cells to respond to peptides derived from foreign proteins while ignoring those from self‐proteins. However, T cells can also respond to peptides derived from proteins that have undergone post‐translational modifications (PTMs). Over 200 different PTMs have been described, and while they are essential for protein function, localization and stability, their dysregulation is often associated with disease conditions. PTMs can affect the proteolytic processing of proteins and prevent MHC binding, thereby changing the repertoire of peptides presented on MHC molecules. However, it is also increasingly evident that many peptides presented on MHC molecules carry PTMs, which can alter their immunogenicity. As a result, the presentation of post‐translationally modified peptides by MHC molecules plays a significant role in various diseases, as well as autoimmune disorders and allergies. This review will provide an overview of the impact of PTMs on antigen presentation and their implications for immune recognition and disease.

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Figure 1 Model of the role of post‐translational modifications (PTMs) in T‐cell cancer recognition. Thymic epithelial cells express tissue‐restricted antigens, but not the enzymes responsible for their PTM such as kinases and glycosyl transferases. Therefore, negative selection only removes T cells recognizing the unmodified major histocompatibility complex (MHC) epitopes. As cancer cells express both the antigen and the enzymes responsible for PTMs, they can be recognized by T cells that recognize the modified epitopes. This figure was created with Biorender.com.
Figure 1 Model of the role of post‐translational modifications (PTMs) in T‐cell cancer recognition. Thymic epithelial cells express tissue‐restricted antigens, but not the enzymes responsible for their PTM such as kinases and glycosyl transferases. Therefore, negative selection only removes T cells recognizing the unmodified major histocompatibility complex (MHC) epitopes. As cancer cells express both the antigen and the enzymes responsible for PTMs, they can be recognized by T cells that recognize the modified epitopes. This figure was created with Biorender.com.CC BY · PubMed Central
Figure 2 Examples of major histocompatibility complex (MHC) class I presentation of epitopes carrying post‐translational modifications of different sizes. Protein structures obtained by X‐ray diffraction of (a) MHC class I HLA‐B*27:05 carrying an epitope derived from SON phosphorylated at two positions [arrowhead and inset; Protein Data Bank (PDB) code: 7DYN]. 116 (b) HLA‐B*27:05 carrying a citrullinated epitope from VIPR (PDB: 3B6S). 56 (c) Murine MHC class I H2‐Kb carrying an epitope from vesicular stomatitis Indiana virus nucleoprotein with an O‐linked glycan (2‐acetamido‐2‐deoxy‐beta‐d‐glucopyranose‐(1–4)‐[alpha‐l‐fucopyranose‐(1–6)]2‐acetamido‐2‐deoxy‐beta‐d‐glucopyranose) (PDB: 1KBG). 59 (d) Rhesus macaque MHC class I molecule Mamu‐B*098 carrying a myristoylated epitope from the Simian immunodeficiency virus protein NEF (PDB: 4ZFZ). 60 (e) HLA‐B*39:01 presenting an epitope from RNA helicase DDX3X with N‐terminal acetylation (PDB: 4O2C). 117 (f) Ubiquitin, plotted at the same scale as the MHC peptide complexes of panels a–e (PDB: 4XOF). 118 For a–e, post‐translational modifications (PTMs) are in orange.
Figure 2 Examples of major histocompatibility complex (MHC) class I presentation of epitopes carrying post‐translational modifications of different sizes. Protein structures obtained by X‐ray diffraction of (a) MHC class I HLA‐B*27:05 carrying an epitope derived from SON phosphorylated at two positions [arrowhead and inset; Protein Data Bank (PDB) code: 7DYN]. 116 (b) HLA‐B*27:05 carrying a citrullinated epitope from VIPR (PDB: 3B6S). 56 (c) Murine MHC class I H2‐Kb carrying an epitope from vesicular stomatitis Indiana virus nucleoprotein with an O‐linked glycan (2‐acetamido‐2‐deoxy‐beta‐d‐glucopyranose‐(1–4)‐[alpha‐l‐fucopyranose‐(1–6)]2‐acetamido‐2‐deoxy‐beta‐d‐glucopyranose) (PDB: 1KBG). 59 (d) Rhesus macaque MHC class I molecule Mamu‐B*098 carrying a myristoylated epitope from the Simian immunodeficiency virus protein NEF (PDB: 4ZFZ). 60 (e) HLA‐B*39:01 presenting an epitope from RNA helicase DDX3X with N‐terminal acetylation (PDB: 4O2C). 117 (f) Ubiquitin, plotted at the same scale as the MHC peptide complexes of panels a–e (PDB: 4XOF). 118 For a–e, post‐translational modifications (PTMs) are in orange.CC BY · PubMed Central

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Metadata

Authors
de Wit, A. S., Bianchi, F., & van den Bogaart, G.
Affiliations
University of Groningen (NL)
Corresponding author
van den Bogaart, Geert
ORCID
Venue
Immunology & Cell Biology
Publisher
Wiley
Published
2024-11-28
Volume
103
Issue
2
Pages
161-177
ISSN
  • 0004-945X (ISSN-L)
  • 0818-9641
  • 1440-1711
DOI
10.1111/imcb.12839
PMC
PMC11792782
OpenAlex
W4404869275
Cited by
12
References
1
Citations by year
2026: 8 · 2025: 4
FWCI
0.47
Type
journal article
Language
en
Open access
Licence
Locations
  • Immunology and Cell Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, cc-by)
Funders
  • H2020 European Research Council (862137)
  • ZonMw (09120011910001)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
post-translational modification, antigen presentation, MHC class I, MHC class II, T cell recognition, self-tolerance, immunogenicity, proteolytic processing, autoimmune disease, allergy
MeSH terms
Animals, Humans, Major Histocompatibility Complex, Peptides, Protein Processing, Post-Translational, Histocompatibility Antigens Class I, Antigen Presentation

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CoChat. (2026). Citation check: Antigen presentation of post‐translationally modified peptides in major histocompatibility complexes. https://app.cochat.ai/papers/10.1111/imcb.12839
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de Wit, A. S., Bianchi, F., & van den Bogaart, G. (2025). Antigen presentation of post‐translationally modified peptides in major histocompatibility complexes. Immunology & Cell Biology. https://doi.org/10.1111/imcb.12839