The immuno-regulatory activity of placentally secreted pregnancy-specific glycoprotein (PSG) 1

Human pregnancy is accompanied by significant changes in the maternal immune system to support the maintenance of a semi-allogenic fetus. The placenta plays an important role in this process by secreting factors into the maternal circulation including the pregnancy-specific glycoproteins (PSGs). Human PSGs are encoded by 10 different genes and frequent copy number variations of the PSG locus (11-30 copies) related to ethnicity have been reported. The PSGs share substantial amino acid sequence similarity, are mainly secreted by syncytiotrophoblasts, and are found in maternal circulation throughout pregnancy. Our laboratory works on the functional characterization of the PSGs and the identification of their ligands. Most of our studies have centered on PSG1, a highly expressed member of the family. The administration of PSG1 has a protective role in several preclinical immune-mediated disease models. We showed that PSG1 activates the latent form of TGF-b1, thereby increasing the number of CD4+ T-regulatory cells. PSG1 also binds to some galectin family members, including galectin 9 (gal-9). Because of the importance of the innate immune cells in pregnancy, we studied whether PSG1 regulates the response of a macrophage cell line designed to monitor NF-kB and AP-1 activation to different toll-like receptor ligands, and investigated its ability to modulate lipopolysaccharides (LPS) and galectin 9-induced pro-inflammatory cytokine secretion in human monocytes. We found that PSG1 competes with the binding of gal-9 to Tim-3 and has anti-inflammatory activity in monocytes and macrophages, highlighting the critical role of PSG1 in regulating both arms of the immune system during pregnancy.