HLA-DM: arbiter conformationis

The recognition by CD4(+) T cells of peptides bound to class II MHC (MHCII) molecules expressed on the surface of antigen-presenting cells is a key step in the initiation of an adaptive immune response. Presentation of peptides is the outcome of an intracellular selection process occurring in dedicated endosomal compartments involving, among others, an MHCII-like molecule named HLA-DM (DM). The impact of DM on the epitope selection machinery has been known for more than 15 years. However, the mechanism by which DM skews the presented repertoire in favour of kinetically stable complexes has remained elusive. Here, a review of the most recent observations in the field is presented, pointing to the possibility that DM decides the survival of a peptide-MHCII complex (pMHCII) on the basis of its conformational flexibility, which is a function of the 'tightness' of interaction between the peptide and the MHCII at a specific region of the binding site.