Human histocompatibility leukocyte antigen (HLA)-DM edits peptides presented by HLA-DR according to their ligand binding motifs.
Human histocompatibility leukocyte antigen (HLA)-DM is a facilitator of antigen presentation via major histocompatibility complex (MHC) class II molecules. In the absence of HLA-DM, MHC class II molecules do not present natural peptides, but tend to remain associated with class II-associated invariant chain peptides (CLIP). Recently, DM was shown to catalyze the release of CLIP from HLA-DR. We have investigated which peptides bound to HLA-DR are vulnerable to release upon encountering DM. By directed substitution of allele-specific anchor residues between CLIP and DR3-cognate peptides and the application of recombinant DM we show that DM catalyzes the release of those peptides bound to HLA-DR3 that do not have appropriate anchor residues and, hence, no optimal ligand binding motif. Thus, HLA-DM acts as a peptide editor, facilitating selection of peptides that stably bind to class II molecules for eventual presentation to the immune system from the pool of available peptides.
van Ham
S M
SM
Human Immunogenetics Laboratory, Imperial Cancer Research Fund, Holborn, London, United Kingdom.
Grüneberg
U
U
Malcherek
G
G
Bröker
I
I
Melms
A
A
Trowsdale
J
J
D000595:Amino Acid Sequence; D017951:Antigen Presentation; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism*; D001665:Binding Sites; D002460:Cell Line; D006681:HLA-D Antigens / Q000235:genetics / Q000378:metabolism*; D015803:HLA-DR3 Antigen / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D010455:Peptides / Q000378:metabolism*; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism; D016415:Sequence Alignment
D000944:Antigens, Differentiation, B-Lymphocyte; C416189:H2-M antigens; D006681:HLA-D Antigens; C084245:HLA-DM antigens; D015803:HLA-DR3 Antigen; D000949:Histocompatibility Antigens Class II; D010455:Peptides; D011994:Recombinant Proteins; C045084:invariant chain