Featured Article - June 2013
Short description: HLA-DO is an MHCII mimic that prevents the association of HLA-DM to MHCII.
Major histocompatibility class II (MHCII) complexes present peptide antigens to T cells as part of a mechanism that allows immune surveillance of self and foreign antigens and activation of an immune response. Two MHCII-like proteins, HLA-DM and HLA-DO in humans, modulate peptide presentation in the endosomes of antigen-presenting cells. HLA-DM catalyzes the removal of a short peptide called CLIP, a remnant of the protein that escorts the MHCII complex from the endoplasmic reticulum to the endosome. Removal of CLIP allows binding of pathogen- and self-derived peptides to the MHCII binding groove. In addition, HLA-DM also promotes the dissociation of weakly bound peptides, ensuring the accumulation of high-affinity peptides. HLA-DO associates with HLA-DM and inhibits its peptide exchange properties, but the exact mechanism was previously unknown.
Using crystallography, mutagenesis and kinetic studies, Stern and colleagues show that HLA-DO is a substrate mimic that binds HLA-DM and inhibits its interaction with MHCII. The crystal structure of the HLA-DO–HLA-DM complex (PDB 4I0P) shows that HLA-DO has an overall topology very similar to classical MHCII molecules and binds HLA-DM in the same region as MHCII. Mutagenesis and peptide-binding kinetic analysis confirm that HLA-DO engages the same residues as MHCII, but binds with higher affinity.
These findings have important implications for how tolerance to self-antigens is maintained and for peptide repertoire modulation. In fact, HLA-DO-deficient mice have a different spectrum of MHCII-bound peptides than wild-type animals, and this is potentially related to differing cellular localization of HLA-DO and HLA-DM. In the multivesicular body, where MHCII complexes associate with peptides, HLA-DM is present in both the inner and outer membranes, while HLA-DO appears only in the latter. This suggests that MHCII molecules on the inner membrane are free to associate with HLA-DM and are consequently loaded with high-affinity peptides, while MHCII molecules on the outer membrane must scavenge for low-affinity peptides. Therefore, the presence of HLA-DO may promote the surface expression of self-peptides, which are of lower affinity than pathogen-derived peptides, and thus contribute to maintenance of tolerance to self.
A.I. Guce et al. HLA-DO acts as a substrate mimic to inhibit HLA-DM by a competitive mechanism.
Nat. Struct. Mol. Biol. 20, 90-98 (2013). doi:10.1038/nsmb.2460