Cutting Edge: H-2DM Is Responsible for the Large Differences in Presentation Among Peptides Selected by I-Ak During Antigen Processing

Abstract

We quantitated the amounts of peptides from hen egg-white lysozyme presented by I-Ak molecules in APC lines. The large chemical gradient of presentation of the four hen egg-white lysozyme epitopes observed in cell lines expressing HLA-DM or H-2DM (referred to in this study as DM) was significantly diminished in the T2.Ak line lacking DM. Differences in levels of presentation between wild-type and DM-deficient APC were observed for all four epitopes, but differences were most evident for the highest affinity epitope. As a result of these quantitative differences in display, presentation of all four epitopes to T cells was impaired in the line lacking DM. The binding affinity of the pool of naturally processed peptides from DM-expressing lines was higher than that from the DM-deficient line. Thus, using a direct biochemical approach in APC, we demonstrate that DM influences the selection of peptides bound to MHC class II by favoring high affinity peptides.

Susceptibility to HLA-DM Protein Is Determined by a Dynamic Conformation of Major Histocompatibility Complex Class II Molecule Bound with Peptide

“…The exchange of CLIP for antigenic peptides is catalyzed by HLA-DM (DM), a nonclassical MHC II molecule (4 -6). The differential effect of DM on different peptides has been shown to play a key role in antigen presentation (7)(8)(9) and epitope selection (10 -15), but the determinants of DM-mediated peptide exchange remain elusive and controversial (16 -26).…”

Small Molecules That Enhance the Catalytic Efficiency of HLA-DM

“…DM substantially accelerates the dissociation of CLIP and thereby facilitates binding of peptides created by limited proteolysis of foreign and self Ags (6 -8). DM also accelerates the dissociation of other MHC class II-bound peptides, and this editing function favors the presentation of high-affinity peptides, an aspect that is important in antimicrobial T cell responses (7)(8)(9)(10)(11). High-affinity peptides are bound to MHC class II molecules with half-lives of several days or even weeks, and display of such peptides over extended periods of time increases the sensitivity of pathogen detection by T cells (12,13).…”

Empty Class II Major Histocompatibility Complex Created by Peptide Photolysis Establishes the Role of DM in Peptide Association

“…The action of DM is not limited to the Class II MHC/CLIP complex and extends to Class II MHCpeptide complexes more generally. Such editing by DM favors presentation to CD4 T cells of those peptides that are most resistant to peptide displacement by DM (9,(11)(12)(13)(14)(15)(16)(17).DM is a membrane-anchored heterodimer that belongs to the extended family of proteins with a MHC fold but lacks a functional peptide-binding groove (18,19). Mutagenesis experiments identified lateral surfaces on DM and DR molecules that are involved in the interaction between the two proteins.…”

“…The action of DM is not limited to the Class II MHC/CLIP complex and extends to Class II MHCpeptide complexes more generally. Such editing by DM favors presentation to CD4 T cells of those peptides that are most resistant to peptide displacement by DM (9,(11)(12)(13)(14)(15)(16)(17).…”