Gène HLA-G : le plus classique des non classiques

Abstract

Le gène HLA-G, gène du complexe majeur d’histocompatibilité de classe I a longtemps été considéré comme « non classique », du fait de son faible polymorphisme, de la restriction tissulaire de son expression (trophoblaste au cours de la grossesse), de son absence de rôle défini. Mais sa structure générale est très voisine de celle des gènes HLA de classe I et on en a trouvé récemment d’assez nombreux allèles ; son expression n’est plus restreinte au seul trophoblaste et, surtout, on a montré qu’il exerçait deux fonctions classiques pour des molécules du CMH : son produit présente de façon restreinte les peptides de molécules étrangères au récepteur de lymphocytes T CD8+ cytotoxiques et se lie aux récepteurs des cellules NK (natural killer), exerçant sur ces cellules un effet, soit stimulateur, soit inhibiteur.

HLA-G is a human MHC class I gene so far considered as non classical, due to its low polymorphism, its trophoblast restricted tissue distribution during pregnancy and its absence of defined functions. A number of recent data clearly show that these three criteria are no longer applicable and that HLA-G is more and more like the classical HLA class I genes. Firstly, apart a shorter cytoplasmic tail, there is nothing unique about the overall structure of the full length HLA-G protein isoform with the alpha1 and alpha2 external domains forming a peptide binding pocket, a beta2m-associated alpha3 domain and the transmembrane and cytoplasmic domains. Secondly, it appears that HLA-G is not oligomorphic. Between three to six different alleles at the amino acid level have been described according to the population studied and many more allelic forms at the nucleotide level due to non-synonymous substitutions. Moreover, a striking linkage disequilibrium between HLA-G and HLA-A alleles have been reported. Thirdly, it appears that HLA-G could be expressed at the protein level in other cell types than extravillous cytotrophoblast cells including blastocyst, some villous trophoblast cells, amnion epithelial cells. Fourthly, the two major functional properties attributed to the classical HLA class I molecules that are 1) restricting element presenting foreign peptides to the T cell receptor of CD8+ cytotoxic T cells and 2) ligand of different inhibitory or stimulatory NK cell receptors inducing either inhibition or stimulation of NK cell lysis, have also been demonstrated for HLA-G. It was shown that HLA-G is capable of binding endogenously processed nonamer peptides and that, in HLA-G transgenic mice, HLA-G functions as a restricting element in a cytotoxic T cell response. Although not completely clarified, a number of different NK cell receptors of both the immunoglobulin and lectin families have been shown to recognize HLA-G and to exhibit either a stimulatory or inhibitory function. These data were obtained on NK cells derived front peripheral blood. We are awaiting similar experiments performed on decidual NK clones that are present at the materno-fetal interface during pregnancy. All of these recent data allow us to propose that <=the HLA-G gene is the more classical among the non-classical<=. [References: 42]