Is MHCII-restricted immunodominance determined by HLA-DM action?

Abstract

Abstract Binding of antigenic peptides to class II MHC molecules (MHCII) and the activity of the “editing” molecule HLA-DM (DM) on the resulting peptide-MHCII complexes are mechanisms critical to immunodominance, yet not fully understood. Our previous results indicate that peptide binding to the human MHCII HLA-DR1 (DR1) is a flexible event in that different thermodynamic components compensate each other to the possible extent to achieve a stable complex, and the energetic mechanism responsible for binding is reflected in the structural lability of the resulting complex. Here we apply our thermodynamic-structural model of peptide binding to sequences derived from HA H1N1, for which a DR1-restricted classification in dominant, sub-dominant, weak and negative has been established. We measured peptide KD and t1/2, and correlated such measurements to the observed level of immunodominance. Our results show that immunodominant peptides have a binding affinity in the micromolar range in the presence and absence of DM, whereas negative and weak showed no binding, with one exception. Interestingly, DM effect on binding affinity is variable for these peptides, altering their affinity values on a sequence-by-sequence basis with no direct correlation to their level of immunodominance. Variations in complex kinetic stability in the absence of DM did not reflect variations in immunodominance, whereas all peptides showed a faster release in presence of DM. Taken together, our results suggest that there is no a unique peptide-binding or kinetic signature, which can be adopted as a proxy for immunodominance. Further investigation in the thermodynamic components of the binding process is required to corroborate or modify these initial conclusions.