Is there a role for HLA-G in the induction of regulatory T cells during the maintenance of a healthy pregnancy?

Abstract

Pregnancy remains an immune challenge for the uterus that has to adapt to a semi-allogeneic fetus using various regulatory mechanisms. Both HLA-G and regulatory Tcells(CD4+ CD25+ FOXP3+ Tregs ) are upregulated in successful pregnancy, but not in abortion. It is unclear if HLA-G plays a role in the upregulation of regulatory cells. We measured the level of both sHLA-G and Treg cells in the blood of healthy pregnant multigravida, unexplained recurrent spontaneous abortions (URSA) and healthy non-pregnant and nulliparous females. We cultured peripheral blood lymphocytes of healthy non-pregnant multigravida females who never had an abortion with lymphocytes of their partners at ratio of 1:1, with and withoutsHLA-Gto detect changes in number ofTreg cells, or relevant cytokines. Soluble HLA-G concentrations and Treg cells percentage were significantly lower in women with URSA as compared to healthy pregnant multigravida women and were comparable to healthy non-pregnant nulliparous women. Percentage of Tregs increased between zero time and mixed lymphocyte cultures (MLC) in both cultures with and without recombinant sHLA-G but no significant difference between the two cultures. When stimulated with sHLA-G the mean extracellular IL-10 concentration was unchanged, while the mean INF-γ concentration was slightly higher with no significant difference. Intracellular TGF-β was higher in CD4+ cells after incubation with sHLA-G. The results of this study are consistent with previous studies on the role of sHLA-G and Treg cells in inducing immune-tolerance in pregnancy. The results also suggest a possible role for HLA-G in the enrichment of Treg cells.