Absence of imprinting of HLA class Ia genes leads to co-expression of biparental alleles on term human trophoblast cells upon IFN-γ induction

Abstract

Human trophoblast cells have developed various efficient regulatory mechanisms to prevent cell surface expression of the classical HLA-A, -B, and (but not always) -C class I molecules. This allows them to escape maternal alloimmune attack during pregnancy. However, recent results have demonstrated that such a lack of expression could be reversed in villous cytotrophoblast cells purified from term placenta by in vitro IFN-gamma treatment. In this context, we investigated whether both maternal and paternal HLA class Ia antigens were co-dominantly expressed in such trophoblast cells. Using polymerase chain reaction sequence-specific primers for HLA-A and HLA-C alleles, we detected transcripts of both paternal and maternal origins, showing that these genes were not affected by genomic imprinting, at least in term placenta. After in vitro IFN-gamma treatment, the polymorphic HLA-A and HLA-B antigens of both parental origins become detectable at the cell surface, as assessed by flow cytometry and/or complement-dependent microtoxicity test. Appearance of paternal antigens on trophoblast cells upon IFN-gamma induction raises the question of the in vivo biological consequences of this phenomena, in term of materno-fetal tolerance and in particular of a potential allogeneic cytotoxic immune response.

Molecular studies of trophoblast HLA‐G: polymorphism, isoforms, imprinting and expression in preimplantation embryo

“…However, since we now find that HLA‐G protein is remarkably conserved it would seem that the paternal expression of this non‐classical HLA class I gene by trophoblast is unlikely to have any significant effect. Maternal MHC class I genes have been found to be imprinted in the rat placenta (43, 44), but in contrast there is co‐dominant expression of paternal and maternal alleles of these classical class I genes in the mouse placenta (45), human placenta (46) and in horse trophoblast (47). One previous report in which a polymorphism in the 3′‐untranslated region of HLA‐G was used showed no evidence of imprinting in the whole human placenta either at first trimester or term (48).…”

Immunology of Pregnancy

“…Trophoblast cells also effectively repress expression of HLA class II antigens, 288 which are used for stimulation of the T-helper cell subset. PREGNANCY AND LACTATION class I HLA with inflammatory cytokines, 290 suggesting that elements within the placenta have a major role in regulating expression of HLA in trophoblast cells. 289 When released from the architectural environment of the normal placenta, purified trophblast cells can be induced to express 6.…”