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

Nat Commun. 2014 Nov 21:5:5369. doi: 10.1038/ncomms6369.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Antigen Presentation
  • Antigen-Presenting Cells / immunology
  • Autoantigens / chemistry
  • Autoantigens / genetics
  • Autoantigens / immunology*
  • Cathepsins / chemistry
  • Histocompatibility Antigens Class II / genetics
  • Histocompatibility Antigens Class II / immunology
  • Humans
  • Immunodominant Epitopes / chemistry
  • Immunodominant Epitopes / genetics
  • Immunodominant Epitopes / immunology*
  • Influenza A Virus, H5N1 Subtype / chemistry
  • Influenza A Virus, H5N1 Subtype / genetics
  • Influenza A Virus, H5N1 Subtype / immunology*
  • Influenza, Human / virology
  • Mass Spectrometry
  • Molecular Sequence Data
  • T-Lymphocytes / immunology*
  • Viral Proteins / chemistry
  • Viral Proteins / genetics
  • Viral Proteins / immunology*

Substances

  • Autoantigens
  • Histocompatibility Antigens Class II
  • Immunodominant Epitopes
  • Viral Proteins
  • Cathepsins