Abstract
BackgroundProteasomes play a central role in the major histocompatibility class I (MHCI) antigen processing pathway. They conduct the proteolytic degradation of proteins in the cytosol, generating the C-terminus of CD8 T cell epitopes and MHCI-peptide ligands (P1 residue of cleavage site). There are two types of proteasomes, the constitutive form, expressed in most cell types, and the immunoproteasome, which is constitutively expressed in mature dendritic cells. Protective CD8 T cell epitopes are likely generated by the immunoproteasome and the constitutive proteasome, and here we have modeled and analyzed the cleavage by these two proteases.ResultsWe have modeled the immunoproteasome and proteasome cleavage sites upon two non-overlapping sets of peptides consisting of 553 CD8 T cell epitopes, naturally processed and restricted by human MHCI molecules, and 382 peptides eluted from human MHCI molecules, respectively, using N-grams. Cleavage models were generated considering different epitope and MHCI-eluted fragment lengths and the same number of C-terminal flanking residues. Models were evaluated in 5-fold cross-validation. Judging by the Mathew's Correlation Coefficient (MCC), optimal cleavage models for the proteasome (MCC = 0.43 ± 0.07) and the immunoproteasome (MCC = 0.36 ± 0.06) were obtained from 12-residue peptide fragments. Using an independent dataset consisting of 137 HIV1-specific CD8 T cell epitopes, the immunoproteasome and proteasome cleavage models achieved MCC values of 0.30 and 0.18, respectively, comparatively better than those achieved by related methods. Using ROC analyses, we have also shown that, combined with MHCI-peptide binding predictions, cleavage predictions by the immunoproteasome and proteasome models significantly increase the discovery rate of CD8 T cell epitopes restricted by different MHCI molecules, including A*0201, A*0301, A*2402, B*0702, B*2705.ConclusionsWe have developed models that are specific to predict cleavage by the proteasome and the immunoproteasome. These models ought to be instrumental to identify protective CD8 T cell epitopes and are readily available for free public use at http://imed.med.ucm.es/Tools/PCPS/.
Highlights
Proteasomes play a central role in the major histocompatibility class I (MHCI) antigen processing pathway
CD8 T cell epitopes and, in general, peptides presented by MHCI molecules, derive from protein fragments produced in the cytosol by the proteolytic action of the
The second dataset included 382 peptides that were eluted from human MHCI molecules, and the third dataset encompassed 137 HIV1-specific CD8 T cell epitopes restricted by human MHCI molecules and naturally processed
Summary
Proteasomes play a central role in the major histocompatibility class I (MHCI) antigen processing pathway They conduct the proteolytic degradation of proteins in the cytosol, generating the C-terminus of CD8 T cell epitopes and MHCI-peptide ligands (P1 residue of cleavage site). Upon IFN-g exposure, the three catalytic subunits of the constitutive 20 S core can be replaced by three new catalytic subunits: b5i (LMP2), b2i (MECL-1), and b1i (LMP2) [11] This new form of proteasome is called immunoproteasome, as opposed to the constitutively expressed proteasome. Because the antigen-specific cytotoxic function of CD8 T cells is generally acquired upon the recognition of MHCI-bound peptide antigens displayed on the cell surface of dendritic cells (priming), it is likely that protective epitopes are those generated by the proteasome and the immunoproteasome [15]
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