Quantitative analysis of MHC class II peptide exchange reveals pivotal role of peptide association rate

MHC-II presents antigenic peptides to T helper cells, thus shaping adaptive immune responses. Peptide loading of MHC-II in endosomes is shaped by the susceptibility of the peptide-MHC-II complex to dissociation by the catalyst HLA-DM. For a given MHC-II allotype, experimental data reveal an enormous range of HLA-DM susceptibilities of different peptides - more than five orders of magnitude. To understand the underlying mechanisms, we develop a coarse-grained kinetic model and confront it with experimental data. The model explains the observed variation of HLA-DM susceptibility with the peptide-MHC-II binding energy by an allosteric competition mechanism. Paradoxically, however, certain peptides are resistant to dissociation by HLA-DM regardless of their binding energy. Our model predicts that this resistance is linked with fast peptide association to MHC-II in the absence of HLA-DM. In sum, our data-based theoretical analysis identifies two distinct molecular mechanisms that shape antigen presentation by MHC-II.