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

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 semimature 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. Keywords: Pregnancy IntroductionDCs are a heterogeneous population of highly specialized APCs recognized for their crucial role as regulators of innate and adaptive immunity. They can also fine tune the context (and hence the outcome) of Ag presentation in response to a plethora of environCorrespondence: Prof. Claudia C. Motrán e-mail: cmotran@fcq.unc.edu.ar mental signals that indicate the presence of pathogens or tissue damage. These signals generally boost DC maturation, which promotes their migration from peripheral tissues to secondary lymphoid organs and increases their capacity to induce and regulate effector T-cell responses. In addition, recent evidence has highlighted a critical role for DCs in promoting tolerance, limiting uncontrolled inflammation and maintaining immune cell homeostasis [1].The DC-derived factors that determine the outcome of DC-T-cell interactions are the levels of Ag presentation, the display of costimulatory molecules, and the presence ofwww.eji-journal.eu 1574 Fernando F. Martínez et al. Eur. J. Immunol. 2012. 42: 1573-1584 immunomodulatory factors such as cytokines. While increased levels of Ag presentation and the expression of costimulatory molecules such as CD80, CD86, and CD40 on DCs are crucial for the expansion of Ag-specific T cells, the expression of coinhibitory molecules, such as programmed cell death-1 (PD-1) ligands, PD-L1 and PD-L2, can act synergistically to inhibit T-cell activation, proliferation, and cytokine production [2]. Regarding the role of cytokine in driving the type of cellular effector response, stimuli that induce IL-12 promote IFN-γ-producing Th1 cells, stimuli that induce IL-10 and T...

Changes in expression of Th1 and Th2 cytokines in bovine peripheral blood mononuclear cells during early pregnancy

“…1). Pregnancyspecific glycoprotein promotes the expansion of IL-5-secreting cells in vivo, which is related with a successful pregnancy (Martínez et al, 2012). It is reported that dendritic cells treated with placental growth factor results in the suppression of naïve CD 4+ T cell proliferation, with an upregulation of IL-5 secretion in the CD 4+ T cell, which is beneficial for pregnancy in human (Lin et al, 2007).…”

Convergent evolution of pregnancy-specific glycoproteins in human and horse

“…Therefore, potent tolerance mechanisms are required to prevent destruction of fetal cells. As PSGs have the capacity to modulate maternal immune responses (Martinez et al 2012, 2013, Falcon et al 2014, we previously suggested that maintenance of immune tolerance is an important selective force in the expansion of PSG gene clusters (Kammerer & Zimmermann 2010). The horse has, similar to swine and cattle, an epitheliochorial placenta in which fetal cells are separated from the maternal immune system.…”

Adaptive Immune Responses During Pregnancy

“…Similarly to what is reported for Gal-1 54 and HO-1 27 among others, PSG1a seems to modulate DC phenotype and maturation that finally promotes the secretion of IL-17. 84 Other PSGs are also of relevance for establishment of pregnancy as elegantly demonstrated by the group of Gabriela Dveksler. 85,86 …”