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HLA-DM stabilizes empty HLA-DR molecules in a chaperone-like fashion
A B vogt1, G Moldenhauer, G J Hämmerling
1Department of Molecular Immunology, German Cancer Research Center, Heidelberg, Germany.
Abstract:
HLA-DM (DM) is a non-classical major histocompatibility complex (MHC) class II molecule that interacts with classical MHC II molecules in acidic compartments. During this association DM is supposed to catalyze the release of invariant chain (II)-derived CLIP peptides thereby rendering the peptide binding groove accessible for antigenic peptide loading. However, in situations of peptide scarcity the fate of these DM:DR complexes is not known. We could show that DR molecules incubated at lysosomal pH in the absence of peptide rapidly undergo functional inactivation and aggregation. In the presence of DM, however, empty DR molecules were shown to be stabilised and kept receptive for peptide loading, with the degree of the stabilising effect of DM varying for different DR alleles. In addition, in lysosomal compartments a considerable fraction of DM was found to be stably associated with empty DR alpha beta dimers thereby preserving their functionality. Upon encounter with antigenic peptide the DM-associated DR molecules could be rapidly loaded, whereupon they did no longer bind to DM. Thus, DM seems to act as a dedicated class II-specific chaperone that rescues uncharged alpha beta dimers. In view of the suggested shortage of self-peptides in the loading compartment, empty class II molecules that are kept receptive for loading by the chaperone function of DM may enable the antigen processing system to respond promptly to the challenge by newly entering antigens.
Insights
HLA-DM (DM) acts as a chaperone for MHC class II molecules, preventing their inactivation in peptide-poor environments. This ensures antigen presentation readiness by stabilizing empty DR molecules for peptide loading.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Major histocompatibility complex (MHC) class II molecules present antigens to T cells.
- HLA-DM (DM) is a non-classical MHC class II molecule involved in peptide loading onto classical MHC II molecules.
- The role of DM in stabilizing MHC II molecules during peptide scarcity was previously unknown.
Purpose of the Study:
- To investigate the fate of MHC class II (DR) molecules in lysosomal compartments under conditions of peptide scarcity.
- To determine the stabilizing effect of HLA-DM (DM) on empty DR molecules.
- To elucidate the chaperone-like function of DM in preserving MHC II functionality.
Main Methods:
- Incubation of DR molecules at lysosomal pH with and without DM.
- Assessment of DR molecule functional inactivation and aggregation.
- Analysis of DM-DR complex formation and stability.
- Evaluation of peptide loading capacity of DM-associated DR molecules.
Main Results:
- Empty DR molecules rapidly inactivate and aggregate at lysosomal pH without DM.
- DM stabilizes empty DR molecules, maintaining their peptide-loading receptivity.
- The stabilizing effect of DM varies among different DR alleles.
- DM forms stable complexes with empty DR alpha beta dimers, preserving their function.
- DM-associated DR molecules are rapidly loaded with antigenic peptides and subsequently release DM.
Conclusions:
- HLA-DM functions as a dedicated chaperone for MHC class II molecules, rescuing uncharged alpha beta dimers.
- DM prevents the inactivation and aggregation of empty DR molecules in peptide-limited environments.
- This chaperone activity ensures that MHC class II molecules remain receptive for prompt antigen loading, enhancing immune response efficiency.