Divergent paths for the selection of immunodominant epitopes from distinct antigenic sources

AeRyon Kim, Isamu Z. Hartman, Brad Poore, Tatiana Boronina, Robert N. Cole, Nianbin Song, M. Teresa Ciudad, Rachel R. Caspi, Dolores Jaraquemada and Scheherazade Sadegh-Nasseri ()
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AeRyon Kim: Johns Hopkins University School of Medicine
Isamu Z. Hartman: The Graduate Program in Immunology, Johns Hopkins University School of Medicine
Brad Poore: Johns Hopkins University School of Medicine
Tatiana Boronina: Mass Spectrometry and Proteomics Facility, The Johns Hopkins University School of Medicine
Robert N. Cole: Mass Spectrometry and Proteomics Facility, The Johns Hopkins University School of Medicine
Nianbin Song: The Graduate Program in Immunology, Johns Hopkins University School of Medicine
M. Teresa Ciudad: Physiology and Immunology, Laboratori d'Immunologia Cellular, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona
Rachel R. Caspi: Laboratory of Immunology, National Eye Institute, NIH
Dolores Jaraquemada: Physiology and Immunology, Laboratori d'Immunologia Cellular, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona
Scheherazade Sadegh-Nasseri: Johns Hopkins University School of Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-16

Abstract: Abstract Immunodominant epitopes are few selected epitopes from complex antigens that initiate T-cell responses. Here to provide further insights into this process, we use a reductionist cell-free antigen-processing system composed of defined components. We use the system to characterize steps in antigen processing of pathogen-derived proteins or autoantigens and we find distinct paths for peptide processing and selection. Autoantigen-derived immunodominant epitopes are resistant to digestion by cathepsins, whereas pathogen-derived epitopes are sensitive. Sensitivity to cathepsins enforces capture of pathogen-derived epitopes by major histocompatibility complex class II (MHC class II) before processing, and resistance to HLA-DM-mediated-dissociation preserves the longevity of those epitopes. We show that immunodominance is established by higher relative abundance of the selected epitopes, which survive cathepsin digestion either by binding to MHC class II and resisting DM-mediated-dissociation, or being chemically resistant to cathepsins degradation. Non-dominant epitopes are sensitive to both DM and cathepsins and are destroyed.

Date: 2014
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DOI: 10.1038/ncomms6369

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