Ligand exchange of major histocompatibility complex class II proteins is triggered by H-bond donor groups of small molecules.
Hydrogen bonds (H-bonds) are crucial for the stability of the peptide-major histocompatibility complex (MHC) complex. In particular, the H-bonds formed between the peptide ligand and the MHC class II binding site appear to have a great influence on the half-life of the complex. Here we show that functional groups with the capacity to disrupt hydrogen bonds (e.g. -OH) can efficiently catalyze ligand exchange reactions on HLA-DR molecules. In conjunction with simple carrier molecules (such as propyl or benzyl residues), they trigger the release of low affinity ligands, which permits the rapid binding of peptides with higher affinity. Similar to HLA-DM, these compounds are able to influence the MHC class II ligand repertoire. In contrast to HLA-DM, however, these simple small molecules are still active at neutral pH. Under physiological conditions, they increase the number of "peptide-receptive" MHC class II molecules and facilitate exogenous peptide loading of dendritic cells. The drastic acceleration of the ligand exchange on these antigen presenting cells suggests that, in general, availability of H-bond donors in the extracellular milieu controls the rate of MHC class II ligand exchange reactions on the cell surface. These molecules may therefore be extremely useful for the loading of antigens onto dendritic cells for therapeutic purposes.
Falk
Kirsten
K
Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Lau
Julie M
JM
Santambrogio
Laura
L
Esteban
Viviana Marin
VM
Puentes
Fabiola
F
Rotzschke
Olaf
O
Strominger
Jack L
JL
D000433:1-Propanol / Q000494:pharmacology; D000818:Animals; D000941:Antigens / Q000737:chemistry; D001665:Binding Sites; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002469:Cell Separation; D003713:Dendritic Cells / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000737:chemistry; D000431:Ethanol / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D005802:Genes, MHC Class II; D006681:HLA-D Antigens / Q000378:metabolism; D006684:HLA-DR Antigens / Q000096:biosynthesis; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D008285:Major Histocompatibility Complex; D051379:Mice; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D013601:T-Lymphocytes / Q000378:metabolism
D000941:Antigens; D000939:Epitopes; D006681:HLA-D Antigens; C084245:HLA-DM antigens; D006684:HLA-DR Antigens; D008024:Ligands; D010455:Peptides; D000431:Ethanol; D000433:1-Propanol