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A platform for mapping reactive cysteines within the immunopeptidome

Author

Listed:
  • Chenlu Zhang

    (Northwestern University)

  • Chen Zhou

    (Northwestern University)

  • Assa Magassa

    (Northwestern University
    Northwestern University)

  • Xiaokang Jin

    (Northwestern University)

  • Deyu Fang

    (Northwestern University Feinberg School of Medicine)

  • Xiaoyu Zhang

    (Northwestern University
    Northwestern University
    Northwestern University
    Northwestern University Feinberg School of Medicine)

Abstract

The major histocompatibility complex class I antigen presentation pathways play pivotal roles in orchestrating immune responses. Recent studies have begun to explore the therapeutic potential of cysteines within the immunopeptidome, such as the use of covalent ligands to generate haptenated peptide neoepitopes for immunotherapy. In this work, we report a platform for mapping reactive cysteines on MHC-I-bound peptide antigens. We develop cell-impermeable sulfonated maleimide probes capable of capturing reactive cysteines on these antigens. Using these probes in chemoproteomic experiments, we discover that cysteines on MHC-I-bound antigens exhibit various degrees of reactivity. Moreover, interferon-gamma stimulation enhances the reactivity of cysteines at position 8 of 9-mer MHC-I-bound antigens. Finally, we demonstrate that targeting reactive cysteines on MHC-I-bound antigens with a maleimide-conjugated Fc-binding cyclic peptide contributes to the induction of antibody-dependent cellular phagocytosis.

Suggested Citation

  • Chenlu Zhang & Chen Zhou & Assa Magassa & Xiaokang Jin & Deyu Fang & Xiaoyu Zhang, 2024. "A platform for mapping reactive cysteines within the immunopeptidome," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54139-8
    DOI: 10.1038/s41467-024-54139-8
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    References listed on IDEAS

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    1. Christopher Szeto & Pirooz Zareie & Rushika C. Wirasinha & Justin B. Zhang & Andrea T. Nguyen & Alan Riboldi-Tunnicliffe & Nicole L. Gruta & Stephanie Gras & Stephen R. Daley, 2022. "Covalent TCR-peptide-MHC interactions induce T cell activation and redirect T cell fate in the thymus," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Keriann M. Backus & Bruno E. Correia & Kenneth M. Lum & Stefano Forli & Benjamin D. Horning & Gonzalo E. González-Páez & Sandip Chatterjee & Bryan R. Lanning & John R. Teijaro & Arthur J. Olson & Denn, 2016. "Proteome-wide covalent ligand discovery in native biological systems," Nature, Nature, vol. 534(7608), pages 570-574, June.
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