Abstract
In healthy individuals, the non-classical MHC molecule HLA-G is only expressed on fetal trophoblast cells that invade the decidua during placentation. We show that a significant proportion of HLA-G at the surface of normal human trophoblast cells is present as a disulphide-linked homodimer of the conventional β2m-associated HLA-I complex. HLA-G is a ligand for leukocyte immunoglobulin-like receptors (LILR), which bind much more efficiently to dimeric HLA-G than to conventional HLA-I molecules. We find that a LILRB1-Fc fusion protein preferentially binds the dimeric form of HLA-G on trophoblast cells. We detect LILRB1 expression on decidual myelomonocytic cells; therefore, trophoblast HLA-G may modulate the function of these cells. Co-culture with HLA-G+ cells does not inhibit monocyte-derived dendritic cell up-regulation of HLA-DR and costimulatory molecules on maturation, but did increase production of IL-6 and IL-10. Furthermore, proliferation of allogeneic lymphocytes was inhibited by HLA-G binding to LILRB1/2 on responding antigen-presenting cells (APC). As HLA-G is the only HLA-I molecule that forms β2m-associated dimers with increased avidity for LILRB1, this interaction could represent a placental-specific signal to decidual APC. We suggest that the placenta is modulating maternal immune responses locally in the uterus through HLA-G, a trophoblast-specific, monomorphic signal present in almost every pregnancy.See accompanying commentary: http://dx.doi.org/10.1002/eji.200737515
Highlights
HLA-G is a non-classical HLA class I (HLA-I) molecule, selectively expressed in healthy individuals by fetal placental trophoblast cells that invade maternal uterine tissues during placentation [1,2,3,4]
Densitometry measurements of complexes detected by G233, MEM-G/ 11, W6/32 and BBM.1 estimate that 40% of the HLA-G molecules are in the dimeric form
We have shown that a significant proportion of HLA-G molecules present at the surface of normal human trophoblast cells in vivo exist as a dimer
Summary
HLA-G is a non-classical HLA class I (HLA-I) molecule, selectively expressed in healthy individuals by fetal placental trophoblast cells that invade maternal uterine tissues during placentation [1,2,3,4]. Minimal polymorphism [6, 7], an endoplasmic reticulum retrieval mechanism [8], and the structure of the peptide-binding groove [9] contribute to a restricted peptide repertoire in vivo [10]. These characteristics argue against a role for HLA-G as a conventional HLA-I molecule presenting pathogen-derived peptides to T cells. Fetal EVT cells invading the decidua and myometrium come into close contact with maternal uterine leukocytes that, in early gestation, are predominantly composed of NK cells, as well as myelomonocytic cells and some T cells [11]
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