Abstract
Galectins are potent immunomodulators that regulate maternal immune responses in pregnancy and prevent the rejection of the semi-allogeneic fetus that also occurs in miscarriages. We previously identified a gene cluster on Chromosome 19 that expresses a subfamily of galectins, including galectin-13 (Gal-13) and galectin-14 (Gal-14), which emerged in anthropoid primates. These galectins are expressed only by the placenta and induce the apoptosis of activated T lymphocytes, possibly contributing to a shifted maternal immune balance in pregnancy. The placental expression of Gal-13 and Gal-14 is decreased in preeclampsia, a life-threatening obstetrical syndrome partly attributed to maternal anti-fetal rejection. This study is aimed at revealing the effects of Gal-13 and Gal-14 on T cell functions and comparing the expression of these galectins in placentas from healthy pregnancies and miscarriages. First-trimester placentas were collected from miscarriages and elective termination of pregnancies, tissue microarrays were constructed, and then the expression of Gal-13 and Gal-14 was analyzed by immunohistochemistry and immunoscoring. Recombinant Gal-13 and Gal-14 were expressed and purified, and their effects were investigated on primary peripheral blood T cells. The binding of Gal-13 and Gal-14 to T cells and the effects of these galectins on apoptosis, activation marker (CD25, CD71, CD95, HLA-DR) expression and cytokine (IL-1β, IL-6, IL-8, IL-10, IFNγ) production of T cells were examined by flow cytometry. Gal-13 and Gal-14 are primarily expressed by the syncytiotrophoblast at the maternal-fetal interface in the first trimester, and their placental expression is decreased in miscarriages compared to first-trimester controls. Recombinant Gal-13 and Gal-14 bind to T cells in a population- and activation-dependent manner. Gal-13 and Gal-14 induce apoptosis of Th and Tc cell populations, regardless of their activation status. Out of the investigated activation markers, Gal-14 decreases the cell surface expression of CD71, Gal-13 increases the expression of CD25, and both galectins increase the expression of CD95 on T cells. Non-activated T cells produce larger amounts of IL-8 in the presence of Gal-13 or Gal-14. In conclusion, these results show that Gal-13 and Gal-14 already provide an immunoprivileged environment at the maternal-fetal interface during early pregnancy, and their reduced expression is related to miscarriages.
Highlights
Our studies have shown that the placental expression of Gal-13 and Gal-14 is down-regulated in preterm preeclampsia [81, 110, 113, 129], where the placental pathology and the pro-inflammatory changes are similar to that of miscarriage [130,131,132,133,134,135]
Immunostainings of tissue microarrays (TMAs) revealed that Gal-13 (Figures 1A,B) and Gal-14 (Figures 1E,F) are predominantly expressed in the cytoplasm of the syncytiotrophoblast of chorionic villi in the first trimester, and there were no stainings in the cytotrophoblasts and villous stroma, similar to later stages of pregnancy [53, 81, 106, 110, 113]
The specificity of the galectin antibodies was confirmed by previous studies and by the lack of Gal-13 and Gal-14 immunostaining of human livers on our TMAs
Summary
The mechanisms sustaining maternal immune tolerance to the semi-allogeneic fetus while shielding against microbial infections during pregnancy as well as the changes and interplay of maternal, fetal, and placental immune responses during pregnancy are of major interest in reproductive research [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41] These immune tolerance mechanisms are complex and dynamic given that implantation involves decidual inflammation; the second trimester of pregnancy is characterized by a predominantly anti-inflammatory milieu in the womb, while at the end of the third trimester, the initiation of parturition requires a transition toward physiologic pro-inflammatory responses [42,43,44]. These three galectins are expressed from a gene cluster on Chromosome 19 that had emerged in anthropoid primates [53, 56, 61, 110]
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