HLA-G GENE - THE MORE CLASSICAL AMONG THE NONCLASSICAL

HLA-G is a human MHC class I gene so far considered as non classical, due to its low polymorphism, its trophoblast restricted tissue distrib ution during pregnancy and its absence of defined functions. A number of recent data dearly show that these three criteria are no longer app licable and that HLA-G is more and more like the classical HLA class I genes. Firstly, apart a shorter cytoplasmic tail, there is nothing un ique about the overall structure of the full length HLA-G protein isof orm with the alpha 1 and alpha 2 external domains forming a peptide bi nding pocket, a beta 2m-associated alpha 3 domain and the transmembran e and cytoplasmic domains. Secondly, it appears that HLA-G is not olig omorphic. Between three to six different alleles at the amino acid lev el have been described according to the population studied and many mo re allelic forms at the nucleotide level due to nonsynonymous substitu tions. Moreover, a striking linkage disequilibrium between HLA-G and H LA-A alleles have been reported. Thirdly, it appears that HLA-G could be expressed at the protein level in other cell types than extravillou s cytotrophoblast cells including blastocyst, some villous trophoblast cells, amnion epithelial cells. Fourthly, the two major functional pr operties attributed to the classical HLA class I molecules that are 1) restricting element presenting foreign peptides to the T cell recepto r of CD8(+) cytotoxic T cells and 2) ligand of different inhibitory or stimulatory NK cell receptors inducing either inhibition or stimulati on of NK cell lysis, have also been demonstrated for HLA-G. It was sho wn that HLA-G is capable of binding endogenously processed nonamer pep tides and that, in HLA-G transgenic mice, HLA-G functions as a restric ting element in a cytotoxic T cell response. Although not completely c larified, a number of different NK cell receptors of both the immunogl obulin and lectin families have been shown to recognize HLA-G and to e xhibit either a stimulatory or inhibitory function. These data were ob tained on NK cells derived from peripheral blood. We are awaiting simi lar experiments performed on decidual NK clones that are present at th e materno-fetal interface during pregnancy. All of these recent data a llow us to propose that << the HLA(-)G gene is the more classical amon g tile non-classicals>>.