Properties of MHC Class I Presented Peptides That Enhance Immunogenicity

Abstract

T-cells have to recognize peptides presented on MHC molecules to be activated and elicit their effector functions. Several studies demonstrate that some peptides are more immunogenic than others and therefore more likely to be T-cell epitopes. We set out to determine which properties cause such differences in immunogenicity. To this end, we collected and analyzed a large set of data describing the immunogenicity of peptides presented on various MHC-I molecules. Two main conclusions could be drawn from this analysis: First, in line with previous observations, we showed that positions P4–6 of a presented peptide are more important for immunogenicity. Second, some amino acids, especially those with large and aromatic side chains, are associated with immunogenicity. This information was combined into a simple model that was used to demonstrate that immunogenicity is, to a certain extent, predictable. This model (made available at http://tools.iedb.org/immunogenicity/) was validated with data from two independent epitope discovery studies. Interestingly, with this model we could show that T-cells are equipped to better recognize viral than human (self) peptides. After the past successful elucidation of different steps in the MHC-I presentation pathway, the identification of variables that influence immunogenicity will be an important next step in the investigation of T-cell epitopes and our understanding of cellular immune responses.

Author Summary

T-cells have to recognize peptides presented on MHC molecules to be activated and elicit their effector functions. Some peptide-MHC-I complexes (pMHCs) are better recognized by T-cells; we call such pMHCs more immunogenic. For other pMHCs, no recognizing T-cells seem to exist; we call such pMHCs non-immunogenic. We set out to determine which properties of pMHCs cause such differences in immunogenicity, by carefully collecting a large set of immunogenic and non-immunogenic pMHCs, and analysing the difference between these sets. Two important observations were made: First, in line with previous observations, we showed that positions P4–6 of a presented peptide are more important for immunogenicity. Second, some amino acids, especially those with large and aromatic side chains, seem to be better recognized by T-cells as they associate with immunogenicity. Next, this information was combined into a simple model to predict the immunogenicity of new pMHCs (this model is made available at http://tools.iedb.org/immunogenicity/). Interestingly, with this model we could show that T-cells are equipped to strongly recognize viral peptides. After the past successful elucidation of different steps in the MHC-I presentation pathway, the identification of variables that influence immunogenicity will be an important next step in the investigation of T-cell epitopes and our understanding of cellular immune responses.