Nonclassical HLA-G molecules are classical peptide presenters.
BACKGROUND
The physiological functions of the classical HLA (human leukocyte antigen) molecules, HLA-A, HLA-B and HLA-C, are to present peptides to T cells and to inhibit the activity of natural killer cells. In contrast, the functions of nonclassical HLA-molecules, such as HLA-E, HLA-F and HLA-G, remain to be established. The expression of HLA-G is largely limited to the placental trophoblast, where it might mediate protection of the fetus from rejection by the mother. Achieving the aim of understanding the function of HLA-G should be facilitated by information on the biochemical properties of HLA-G molecules, especially on their potential ability to act as peptide receptors.


RESULTS
To study peptide presentation by HLA-G, we used stably transfected LCL721.221 cells as a source of HLA-G molecules and analysed the spectrum of extracted peptides by individual and pool sequencing. Our results indicate that HLA-G molecules, like classical HLA molecules, are associated with a wide array of peptides derived from cellular proteins. Peptides presented by HLA-G usually consisted of 9 amino acids, and adhered to a specific sequence motif, with anchor residues at position 2 (isoleucine or leucine), position 3 (proline) and the carboxy-terminal position 9 (leucine). Thus, the HLA-G peptide ligand motif follows the principles of classical HLA motifs, although it displays its own unique features. Peptide-binding assays indicated that two of the three anchor residues were sufficient for binding, and that the three natural HLA-G ligands that we identified bound, not only to HLA-G, but also to HLA-A2. This was not surprising, because the binding pockets of HLA-A2 and HLA-G overlap in their ability to recognize anchor residues at positions 2 and 9. Likewise, some, but not all, HLA-A2 peptide ligands could also bind to HLA-G.


CONCLUSIONS
Nonclassical HLA-G molecules present peptides essentially in the same way as classical HLA molecules do. We determined the peptide motif that is specifically recognized by HLA-G; its basic features are described by the sequence XI/LPXXXXXL: This information should help to elucidate the physiological role of HLA-G molecules at the fetal-maternal interface. Most likely, this role is to protect fetal cells from lysis by natural killer cells, and possibly to present foreign peptides to a class of T cells that has not yet been identified.
Diehl
M
M
Abteilung Tumorvirus-Immunologie (0620), Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany.
Münz
C
C
Keilholz
W
W
Stevanović
S
S
Holmes
N
N
Loke
Y W
YW
Rammensee
H G
HG
D000595:Amino Acid Sequence; D017951:Antigen Presentation; D002461:Cell Line, Transformed; D006680:HLA Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology* / Q000302:isolation & purification; D014162:Transfection
D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; D008024:Ligands; D010455:Peptides