Secretion of pro-apoptotic intron 4-retaining soluble HLA-G1 by human villous trophoblast

Abstract

One major materno‐fetal interface in the human placenta is constituted by the syncytiotrophoblast, in contact with maternal blood of the intervillous space, which derives from differentiation and fusion of the villous cytotrophoblast (vct). In the present work, we purified vct from term placenta by depleting HLA class I‐ and class II‐positive cells. We found by RT‐PCR that both soluble intron 4‐retaining HLA‐G1 (sHLA‐G1) and HLA‐G2 isoforms were transcribed in purified vct. Using different HLA‐G‐specific mAb, we demonstrated by intracellular flow cytometry, Western blotting and ELISA, that sHLA‐G1 but no soluble HLA class Ia molecule was secreted by vct. We then purified sHLA‐G1 from vct culture supernatant and found that it exhibited an unusual glycosylation pattern. Finally, we showed that such trophoblast‐derived sHLA‐G1 triggered specific apoptosis of activated CD8+ T cells. Taken together, these results demonstrated that vct did secrete functional sHLA‐G1 in primary culture and suggested that, in vivo, sHLA‐G1 might be an important immunomodulatory molecule controlling the activity of maternal immune effector CD8+ cells circulating in the blood that immerses chorionic villi.

HLA-G1-expressing antigen-presenting cells induce immunosuppressive CD4+T cells

“…Even though in our system, membrane-bound HLA-G1 had a vastly predominant inhibitory effect over that of sHLA-G1, it was shown that sHLA-G1 induced the apoptosis of activated CD8 ϩ natural killer and T cells (37,38). It is therefore possible that HLA-G1 shedding by HLA-G1 APCs induce a long-term antigen-specific unresponsiveness apparently similar to T cell anergy.…”

Alloreactive CD4+ and CD8+ T cells express the immunotolerant HLA‐G molecule in mixed lymphocyte reactions: in vivo implications in transplanted patients

“…We focused our study on the two main HLA-G isoforms, namely the membrane-bound HLA-G1 and the soluble HLA-G5 proteins. In physiological conditions, both isoforms are expressed at the fetal-maternal interface in trophoblast where they act as specific immunosuppressors and prevent the rejection of the semiallogeneic fetus by the maternal immune system [9][10][11].…”

“…Initially detected at the fetal-maternal interface, the expression of HLA-G protects the fetal semi-allograft from rejection by the mother's immune system [9][10][11]. In non-pathological conditions, HLA-G expression is restricted to immunoprivileged sites such as trophoblast and thymus.…”

“…HLA-G leader peptide stabilizes the cell-surface expression of another non-classical HLA class I inhibitory molecule, HLA-E [20]. Finally, soluble HLA-G induces apoptosis of CD8 + T and NK cells through ligation with CD8, and via a Fas/FasLdependent mechanism [11,21,22].…”

Human immunodeficiency virus 1 downregulates cell surface expression of the non-classical major histocompatibility class I molecule HLA-G1

“…Thus, recognition of HIV-1-infected cells by CD8 + CTL and/or natural killer cells (Lopez-Botet et al, 2000) and survival of these cells may, at least in part, depend on HLA-G1 expression levels. Future experiments will determine whether changes in the expression of different isoforms of HLA-G1, including soluble, could limit or favour HIV spreading through the host or the placenta, where HLA-G1 is highly expressed (Le Bouteiller & Blaschitz, 1999;Solier et al, 2002;Ishitani et al, 2003).…”