The functionality of HLA-G is emerging.

In view of the recently published data, the HLA-G class Ib gene appears to be a functional locus. This is based on the following observations: 1) HLA-G is capable of presenting nonamer peptides and of exerting antigen-presenting functions; 2) HLA-G is a ligand for at least three natural killer (NK) and other cell inhibitory receptors of the immunoglobulin superfamily, namely leukocyte immunoglobulin-like receptor-1/immunoglobulin-like transcript (ILT)-2, ILT-4 and p49; 3) in addition to the extravillous cytotrophoblast cells, HLA-G proteins have been detected in endothelial cells of placental chorionic villi, as well as in amniotic fluid and in some medullary thymic epithelial cells; 4) major histocompatibility complex (MHC) class Ib genes that share the unique characteristics of HLA-G, including a high expression in placenta, have been reported in other mammalian species. In addition to the classical MHC class I roles (antigen presentation and ligation to NK receptors inducing inhibitory and/or activatory signals), HLA-G is likely to exert other, novel functions: first, HLA-G was shown to be involved in the control of HLA-E expression by furnishing the appropriate class I leader sequence nonamer peptide; second, we hypothesize that HLA-G could be a regulator of placental angiogenesis; third, soluble HLA-G isoforms may act as specific immunosuppressors during pregnancy. Such functional properties, although incompletely understood, are likely to be important in the outcome of human pregnancies but also in normal adult life.