Trends in Immunology
ReviewMechanisms of peptide repertoire selection by HLA-DM
Section snippets
MHC class II pathway
When an infectious agent enters the body at a localized anatomical site, the small number of naïve T cells available for a particular pathogen-derived peptide (20– approximately 200 CD4 T cells in mice) need to locate the relevant antigen-presenting cells (APCs) [1]. This search operation requires that relevant peptides are displayed for sufficient periods of time on the surface of APCs for interaction with naïve T cells. MHC class II (MHCII) molecules have evolved to present peptides for
DM-mediated peptide repertoire selection
DM was discovered by characterization of mutant Epstein–Barr-virus-transformed B cell lines with a severe but incomplete defect in antigen presentation by multiple human MHCII molecules (HLA-DR, HLA-DQ, and HLA-DP) [7]. MHCII molecules have a strong tendency to aggregate when the binding groove is not occupied by peptides. They assemble in the endoplasmic reticulum (ER) with the invariant chain, which protects the binding groove until MHCII-invariant chain complexes reach the late endosomal
DM binds a short-lived MHCII conformer
Much effort has been devoted to determine the molecular mechanism for the three functional properties of DM described above: destabilization of all MHCII–peptide complexes including those formed with CLIP; stabilization of an empty MHCII groove; and editing of the peptide repertoire. DM has a similar domain organization as MHCII proteins, but lacks the ability to bind peptides [5]. Extensive mutagenesis experiments on HLA-DR (DR, a human MHCII protein) and DM identified large lateral surfaces
Crystal structure of the DR1–DM complex
These functional studies enabled crystallization of this important complex [17]. An N-terminally truncated peptide was covalently linked to the DR1 molecule, through a disulfide bond in the P6 pocket. Furthermore, the β chains of DM and DR1 were linked using sortase A to mimic membrane tethering of DM and DR (which enhances the interaction between the two molecules) 17, 18.
The structure shows that the interaction is dominated by the DRα and DMα chains (Figure 1), and there is also a smaller
Inhibition of DM by DO
HLA-DO (H-2O in mice) has a similar structural organization as classical MHCII molecules and more sequence similarity to MHCII proteins (∼60%) than DM (∼28%). The assembly of DO heterodimers is inefficient in the absence of DM, and DM is needed for egress from the ER. DO forms long-lived complexes with DM and inhibits the catalytic activity of DM [20]. Its expression is specifically downregulated in germinal center B cells relative to naïve B cells, enhancing MHCII antigen presentation by
Why does DO fail to bind peptides?
The recent crystal structure of the DO–DM complex shows that DO is indeed an MHCII homolog and inhibits DM function by acting as a substrate mimic 25, 26. The overall topology of DO is similar to that of classical MHCII proteins. Despite this similarity, the groove flanked by the DOα and β helices is empty in the structure of the DO–DM complex. Why does DO apparently not bind peptide, despite structural similarity to MHCII molecules? As mentioned above, peptide binding by all MHCII proteins
How does DM interact with DR or DO?
DO functions as a competitive and essentially irreversible inhibitor of DM activity. DM is expressed at a higher level than DO, which results in a mix of free DM (active) and DO–DM complexes (inactive) [20]. As a substrate mimic, DO interacts with a similar surface of DM as DR1. However, DR1 and DO differ at several positions at their interface with DM (Figure 4). A conserved feature among DO–DM and DR1–DM complexes is the interaction between DR and DOα W43 with DMα N125 17, 25. However, there
Relevance to peptide selection by MHC class I (MHCI) molecules
Both MHCI and MHCII molecules are highly unstable in the absence of peptide. In fact, recombinant MHCI molecules can only be refolded from the relevant subunits (extracellular domain of MHCI heavy chain and β2-microglobulin) in the presence of a peptide. Even though MHCI and MHCII proteins acquire peptides in different compartments and utilize different proteins to facilitate the loading process, there are important similarities in the general requirements for peptide acquisition. The MHCI
Relevance to pathogenesis of autoimmunity
A substantial number of polymorphic HLA-DQ and HLA-DP residues are located at the putative interface with DM. It has already been shown that HLA-DQ2, which is associated with susceptibility to type 1 diabetes and celiac disease interacts poorly with DM 11, 29, 30. This raises the question whether insufficient editing of low-affinity peptides may predispose to certain autoimmune diseases. This hypothesis is supported by the fact that key T cell epitopes in animal models of type 1 diabetes and
Concluding remarks
These results provide a structural foundation for understanding key processes in antigen presentation by MHCII molecules. It has long been thought that DM forces peptide dissociation by changing the conformation of MHCII–peptide complexes. The new studies reveal that DM only binds to a short-lived transition state in which part of the MHCII groove is already empty. DM stabilizes this site and favors a rapid exchange process for selection of the highest-affinity ligands. This process removes
Acknowledgments
We would like to thank Melissa J. Call, Monika-Sarah E. D. Schulze, Anne-Kathrin Anders, Jason Pyrdol, and Eric J. Sundberg for their important contributions to work reviewed here. This work was supported by grants from the National Institutes of Health (RO1 NS044914 and PO1 AI045757 to K.W.W.), postdoctoral fellowships from The National Multiple Sclerosis Society (D.K.S.) and the American Diabetes Association (W.P.).
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