Pregnancy-specific glycoprotein 1a activates dendritic cells to provide signals for Th17-, Th2-, and Treg-cell polarization.

Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
European Journal of Immunology (Impact Factor: 4.52). 06/2012; 42(6):1573-84. DOI: 10.1002/eji.201142140
Source: PubMed

ABSTRACT Because of their plasticity and central role in orchestrating immunity and tolerance, DCs can respond to pregnancy-specific signals, thus promoting the appropriate immune response in order to support pregnancy. Here, we show that pregnancy-specific glycoprotein (PSG1a), the major variant of PSG released into the circulation during pregnancy, targets DCs to differentiate into a subset with a unique phenotype and function. This semi-mature phenotype is able to secrete IL-6 and TGF-β. PSG1a also affected the maturation of DCs, preventing the up-regulation of some costimulatory molecules, and inducing the secretion of TGF-β or IL-10 and the expression of programmed death ligand 1 (PD-L1) in response to TLR-9 or CD40 ligation. In addition, PSG1a-treated DCs promoted the enrichment of Th2-type cytokines, IL-17-producing cells, and Treg cells from CD4(+) T cells from DO11.10 Tg mice. Moreover, in vivo expression of PSG1a promoted the expansion of Ag-specific CD4(+) CD25(+) Foxp3(+) Treg cells and IL-17-, IL-4-, IL-5-, and IL-10-secreting cells able to protect against Listeria monocytogenes infection. Taken together, our data indicate that DCs can be targeted by PSG1a to generate the signals necessary to mount an appropriate, well-balanced, and effective immune response able to protect against invading pathogens while at the same time being compatible with a successful pregnancy.

1 Bookmark
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Transforming growth factor-βs (TGF-βs) are secreted from cells as latent complexes and the activity of TGF-βs is controlled predominantly through activation of these complexes. Tolerance to the fetal allograft is essential for pregnancy success; TGF-β1 and TGF-β2 play important roles in regulating these processes. Pregnancy-specific β-glycoproteins (PSGs) are present in the maternal circulation at a high concentration throughout pregnancy and have been proposed to have anti-inflammatory functions. We found that recombinant and native PSG1 activate TGF-β1 and TGF-β2 in vitro. Consistent with these findings, administration of PSG1 protected mice from dextran sodium sulfate (DSS)-induced colitis, reduced the secretion of pro-inflammatory cytokines, and increased the number of T regulatory cells. The PSG1-mediated protection was greatly inhibited by the coadministration of neutralizing anti-TGF-β antibody. Our results indicate that proteins secreted by the placenta directly contribute to the generation of active TGF-β and identify PSG1 as one of the few known biological activators of TGF-β2.Mucosal Immunology advance online publication, 14 August 2013; doi:10.1038/mi.2013.53.
    Mucosal Immunology 08/2013; · 7.54 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pregnancy-specific glycoproteins (PSGs) are immunoglobulin superfamily members encoded by multigene families in rodents and primates. In human pregnancy, PSGs are secreted by the syncytiotrophoblast, a fetal tissue, and reach a concentration of up to 400 ug/ml in the maternal bloodstream at term. Human and mouse PSGs induce release of anti-inflammatory cytokines such as IL-10 and TGFβ1 from monocytes, macrophages, and other cell types, suggesting an immunoregulatory function. RGD tri-peptide motifs in the majority of human PSGs suggest that they may function like snake venom disintegrins, which bind integrins and inhibit interactions with ligands. We noted that human PSG1 has a KGD, rather than an RGD motif. The presence of a KGD in barbourin, a platelet integrin αIIbβ3 antagonist found in snake venom, suggested that PSG1 may be a selective αIIbβ3 ligand. Here we show that human PSG1 binds αIIbβ3 and inhibits the platelet - fibrinogen interaction. Unexpectedly, however, the KGD is not critical as multiple PSG1 domains independently bind and inhibit αIIbβ3 function. Human PSG9 and mouse Psg23 are also inhibitory suggesting conservation of this function across primate and rodent families. Our results suggest that in species with haemochorial placentation, in which maternal blood is in direct contact with fetal trophoblast, the high expression level of PSGs reflects a requirement to antagonise abundant (3 mg/ml) fibrinogen in the maternal circulation, which may be necessary to prevent platelet aggregation and thrombosis in the prothrombotic maternal environment of pregnancy.
    PLoS ONE 01/2013; 8(2):e57491. · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: ProblemThe contribution of Pregnancy-specific glycoproteins (PSG), the major variant of PSG released into the circulation during pregnancy, to the pregnancy-dependent improvement of rheumatoid arthritis (RA) has still not been elucidated.Method of studyCollagen-induced arthritis (CIA) was used to test the hypothesis that PSG1a when released into circulation has a modulatory role on the Th1-pathogenic response, thus improving the CIA symptoms. In vivo expression of PSG1a was induced by injection of the vaccinia (Vac)-based expression vector harboring the complete open-reading frame of PSG1a cDNA.ResultsIn vivo PSG1a expression during the induction of CIA ameliorated the clinical symptoms, thereby reducing the arthritis score and incidence. Significantly lower levels of IL-17, IL-6, and IFN-γ, but higher levels of TGF-β and IL-10 were secreted by collagen type II-stimulated spleen mononuclear cells from Vac-PSG1a-treated mice compared with control mice. Moreover, Vac-PSG1a treatment promoted the increase in splenic CD4+CD25+Foxp3+ Treg cells.Conclusion Pre-clinical Vac-PSG1a treatment suppressed the Th1- and Th17-type-specific responses, leading to an increase in splenic Treg cells as well as IL-10- and TGF-β-secreting cells, with the CIA symptoms being ameliorated.
    American Journal Of Reproductive Immunology 08/2014; · 3.32 Impact Factor

Full-text (2 Sources)

Available from
Dec 3, 2014