70-kDa heat shock proteins: specific interactions with HLA-DR molecules and their peptide fragments.
Heat shock protein 70 (HSP70):peptide complexes are involved in MHC class I and class II-restricted antigen presentation enabling enhanced activation of antigen-specific T cells. Here, we investigated the potential of bacterial and mammalian HSP70 molecules to interact with peptide fragments from HLA-DR and the corresponding complete HLA-DR molecules. Peptide fragments were found to interact with DnaK, the HSP70 homologue from E. coli, but less with stress-inducible human Hsp70. Only a peptide sequence exclusively found in rheumatoid arthritis-protective HLA-DR molecules did not interact with DnaK. Subsequently, we investigated the interaction of complete HLA-DR molecules with HSP70 and detected a specific HSP70:HLA-DR interaction, with highest affinity for human stress-inducible Hsp70. In contrast to the peptide fragments, no allele-specific differences in Hsp70 affinity were detected with complete HLA-DR molecules. Interaction with HLA-DR molecules was increased at lowered pH values, whereas HSP70-chaperoned peptides were released at acidic pH, thus HSP70 could serve as scanner and carrier for antigenic peptides of self or foreign origin and transfer chaperoned peptides onto MHC class II molecules in acidic late endosomal compartments. Our findings indicate that direct interaction between mammalian HSP70 and HLA-DR molecules could be involved in the HSP70-mediated enhancement of MHC class II-restricted peptide presentation and CD4(+) T cell activation.
Haug
Markus
M
Children's Hospital, University of Tuebingen, Tuebingen, Germany.
Schepp
Carsten P
CP
Kalbacher
Hubert
H
Dannecker
Guenther E
GE
Holzer
Ursula
U
D000595:Amino Acid Sequence; D002461:Cell Line, Transformed; D006684:HLA-DR Antigens / Q000378:metabolism*; D059811:HLA-DRB1 Chains; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary
D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D018840:HSP70 Heat-Shock Proteins; D010446:Peptide Fragments