Exogenous antigens bind MHC class II first, and are processed by cathepsins later

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Graphical abstract

Pathogen-derived antigens bind to MHC class II as full-length proteins or large fragments, while DM facilitates the selection of the best fitting epitopes. As such, the best fitting epitopes form compact dimers with MHC II that do not dissociate by DM. Being insensitive to DM-mediated dissociation rescues those epitopes from being cleaved into peptides too short to form stable complexes with MHC II by cathepsins. Non-dominant epitopes are sensitive to DM-mediated dissociations, and to degradation by cathepsins; they dissociate from MHC II groove by DM, and are destroyed by cathepsins. As such, dominant epitopes/MHC II complexes accumulate and become relatively more abundant. Cathepsins are shown as scissors, peptides and epitopes are depicted as part of the denatured proteins, or in short stretches of sequences that carry a MHC II P1 fitting anchor or no anchor. Small dots represent degraded peptides.

The field of antigen processing and presentation is likely one of the most well defined areas in immunology based on decades of intense molecular and structural studies. Many molecules contributing to antigen processing and presentation have been discovered and their mechanisms of action been largely defined, yet a major question, which lies at the very core of the field has remained hard to pin down. The question is what determines immunodominance? Immunodominance is defined as a few specific epitopes being selected to represent an antigen to the immune system and provide targets for T cells. Many studies have aimed at understanding how epitopes are selected. A range of hypotheses related to the structural features of antigens, sensitivity to proteases, epitope affinity for MHC II, T cell precursor frequency, and T cell receptor affinity for peptide/MHC II have been considered. However, because of the variety of proteins and factors involved in antigen processing and enormous complexity, finding an answer has been challenging. Here we make an effort to tease out the sequence of events in antigen processing that promote selection of immunodominant epitopes for exogenous antigens.

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