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

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) prior to 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.

Proteolysis by Granzyme B Enhances Presentation of Autoantigenic Peptidylarginine Deiminase 4 Epitopes in Rheumatoid Arthritis

“…16–18 As such, flexible strands in a protein are more accessible to the antigen processing machinery and are susceptible to proteolysis by antigen processing enzymes or capture by MHC class II molecules. 14–16,36 For assessing the effects that GrB-induced structural changes have on PAD4 antigen processing, a reductionist cell-free MHC class II antigen processing system, which has proven to be sufficient for processing of full-length antigens and identifying immunodominant epitopes, was utilized.…”

Distorted Immunodominance by Linker Sequences or other Epitopes from a Second Protein Antigen During Antigen-Processing

“…For this epitope to be successfully captured by DR1, we must let DR1 to capture it first, before exposure to the cathepsins mixture. A slightly different case is observed for H5N1-HA1 protein: traces of the dominant epitope of H5N1-HA1 protein remains while the protein is exposed to the cathepsin mixture in the absence of DR1 and DM33. Hence, it is likely that H5N1-HA1(259–274) epitope wins the competition in the race for binding to the MHC II groove, because it is less accessible to digestion by the cathepsins present within antigen processing compartments.…”

“…Despite its minimalist nature, the system can capture physiologically relevant DR1-restricted immunodominant epitopes from several protein antigens, which proved immunodominant in vivo , as determined in DR1 transgenic mice and in DR1 + humans213334. Moreover, the system was shown to be well suited for dissecting steps in antigen processing and in evaluating the factors that contribute to immunodominance3335363738. By using this reductionist antigen processing system, we have learned some unexpected principles of immunodominance.…”

Determinants of immunodominance for CD4 T cells

“…While evidence for both models exist in literature, a recent report applying the reductionist, cell free antigen processing system, discussed earlier, to several antigens derived from pathogens or autoantigens, and provided convincing data that antigen processing of pathogen-derived proteins or autoantigens follow distinct paths. Autoantigen-derived immunodominant epitopes were shown to be resistant to digestion by cathepsins, whereas pathogen-derived epitopes were sensitive [19]. Accompanied by direct evidence for epitope capture to precede cathepsin digestion for pathogen derived epitopes, authors favored the epitope capture model; and by showing that autoantigen-derived core dominant epitopes were resistant to further proteolysis by the cathepsins they strengthened the ‘ cut first, bind later’ model [19].…”

“…Autoantigen-derived immunodominant epitopes were shown to be resistant to digestion by cathepsins, whereas pathogen-derived epitopes were sensitive [19]. Accompanied by direct evidence for epitope capture to precede cathepsin digestion for pathogen derived epitopes, authors favored the epitope capture model; and by showing that autoantigen-derived core dominant epitopes were resistant to further proteolysis by the cathepsins they strengthened the ‘ cut first, bind later’ model [19]. …”