"Chemical analogues" of HLA-DM can induce a peptide-receptive state in HLA-DR molecules.
We had recently identified small molecular compounds that are able to accelerate the ligand exchange reactions of HLA-DR molecules. Here we show that this acceleration is due to the induction of a "peptide-receptive" state. Dissociation experiments of soluble HLA-DR2.CLIP (class II-associated invariant chain peptide) complex and peptide-binding studies with "nonreceptive" empty HLA-DR1 and -DR2 molecules revealed that the presence of a small phenolic compound carrying an H-bond donor group (-OH) results in the drastic increase of both off- and on-rates. The rate-limiting step for ligand exchange, the transition of the major histocompatibility complex molecule from a nonreceptive into the receptive state, is normally mediated by interaction with the chaperone HLA-DM. In this respect, the effect of small molecules resembles that of the natural catalyst, except that they are still active at neutral pH. These "chemical analogues" of HLA-DM can therefore modulate the response of CD4+ T cells by editing the antigen composition of surface-bound class II major histocompatibility complex on living antigen-presenting cells.
Marin-Esteban
Viviana
V
Max Delbrück Center for Molecular Medicine, Robert Rösslestrasse 10, 13125 Berlin, Germany.
Falk
Kirsten
K
Rötzschke
Olaf
O
D000818:Animals; D017951:Antigen Presentation; D000941:Antigens / Q000737:chemistry; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000378:metabolism; D005802:Genes, MHC Class II; D006681:HLA-D Antigens / Q000737:chemistry* / Q000378:metabolism; D006684:HLA-DR Antigens / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008024:Ligands; D051379:Mice; D008956:Models, Chemical; D010455:Peptides / Q000737:chemistry*; D019800:Phenol / Q000737:chemistry; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry; D020349:Surface Plasmon Resonance; D013997:Time Factors
D000941:Antigens; D006681:HLA-D Antigens; C084245:HLA-DM antigens; D006684:HLA-DR Antigens; D008024:Ligands; D010455:Peptides; D011994:Recombinant Proteins; D019800:Phenol