How HLA-DM affects the peptide repertoire bound to HLA-DR molecules.
Considerable progress has been made in the field of major histocompatibility complex (MHC) class II-restricted antigen presentation. The analysis of mutant cell lines defective in antigen presentation revealed a central role for the nonclassical MHC class II molecule HLA-DM. Cell biological and biochemical characterization of HLA-DM provided deeper insight into the molecular mechanisms underlying the loading process: HLA-DM accumulates in acidic compartments, where it stabilizes classical class II molecules until a high-stability ligand occupies the class II peptide binding groove. Thus, HLA-DM prevents empty alpha beta dimers from functional inactivation at low endosomal/lysosomal pH in a chaperone-like fashion. In the presence of peptide ligands, HLA-DM acts as a catalyst for peptide loading by releasing CLIP, the residual invariant chain-derived fragment by which the invariant chain is associated with the class II molecules during transport from the endoplasmic reticulum to the loading compartments. Finally, there is accumulating evidence that HLA-DM functions as a peptide editor that removes low-stability ligands, thereby skewing the class II peptide repertoire toward high-stability alpha beta: peptide complexes presentable to T cells.
Vogt
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AB
Department of Molecular Immunology, German Cancer Research Center, Heidelberg, Germany.
Kropshofer
H
H
Hämmerling
G J
GJ
D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology* / Q000502:physiology*; D001692:Biological Transport / Q000276:immunology; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006681:HLA-D Antigens / Q000235:genetics / Q000276:immunology* / Q000502:physiology*; D006684:HLA-DR Antigens / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D006801:Humans; D010455:Peptides / Q000276:immunology* / Q000378:metabolism
C416189:H2-M antigens; D006681:HLA-D Antigens; C084245:HLA-DM antigens; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; D010455:Peptides