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Keywords:

  • Dendritic cells;
  • macrophages;
  • Th1/Th2 cells;
  • Th17 cells;
  • Tolerance;
  • Treg cells

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pregnancy-specific glycoproteins
  5. Effect of in vivo expression of PSG1a on the adaptive T-cell response
  6. PSGs modulate the immune system through their interaction with professional antigen-presenting cells
  7. PSG1a modulates the metabolism and cytokine secretion by monocyte/macrophage (MΦ) populations
  8. PSG1a targets DCs to differentiate into a subset with a unique phenotype and function
  9. Conclusions
  10. References

Among several explanations for the acceptance of the fetus, the one that suggests that the maternal immune system is suppressed or modified has been the subject of many studies. Thus, it has been proposed that the cells of innate immune system might be able to distinguish the pregnant from the non-pregnant state producing a signal, the so-called signal P. We have previously proposed that pregnancy-specific glycoprotein 1a (PSG1a), a representative member of the main glycoprotein family secreted by placental trophoblast, may modulate the activation of antigen-presenting cells promoting the T-cell shift of the maternal cell immunity toward a less harmful phenotype. In this review, we summarize current knowledge concerning the contribution of pregnancy-specific glycoprotein 1a (PSG1a) to modulate the maternal innate and adaptive immune response in order to assure a successful pregnancy.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pregnancy-specific glycoproteins
  5. Effect of in vivo expression of PSG1a on the adaptive T-cell response
  6. PSGs modulate the immune system through their interaction with professional antigen-presenting cells
  7. PSG1a modulates the metabolism and cytokine secretion by monocyte/macrophage (MΦ) populations
  8. PSG1a targets DCs to differentiate into a subset with a unique phenotype and function
  9. Conclusions
  10. References

The effective defense against infections requires the ability to mount an appropriate and controlled specific immune response able to eradicate the invading pathogen while limiting the collateral damage to self tissues that can result from an exacerbated immune response. The development of an effective type of immune response to eradicate the infection depends primarily on the type of pathogen, and therefore, the pathogen is the main factor skewing the adaptive immune response in a particular direction.[1] The key players that transmit this information are antigen-presenting cells (APCs) such as macrophages (MΦ) and dendritic cells (DCs) that through the innate immune receptors sense the pathogen-associated molecular patterns (PAMPs) present in the microbes and produce surface and secreted proteins that are required together with the antigen to activate naïve T lymphocytes to proliferate and differentiate into effector cells.[2] In addition to the PAMPs that mediate MΦ and DC activation, tissue-derived environmental factors can influence these cells activation and thereby skew the type of adaptive immune response that is initiated by APCs. Depending on the signals transmitted by activated APCs, naïve CD4+ T cells can differentiate into different types of Th cells, which can be distinguished by their cytokine secretion pattern. Th1 cells produce interferon IFN-γ and TNF and are involved in cellular immunity, while Th2 cells, involved in humoral immunity, are characterized by the production of interleukin (IL)-4, IL-5, and IL-10.[3] More recently, a subset of T cells that produce the pro-inflammatory cytokine IL-17 and plays a critical role in the pathogenesis of autoimmune diseases and rejection have been identified.[4-6] In addition, Th17 cells participate in the host defense against bacteria, fungi, and viruses.[7] The function of effector T cells (Th1, Th2, and Th17 cells) is regulated by CD4+ CD25+ regulatory T (Treg) cells, an heterogeneous population important for the maintenance of peripheral tolerance that have the capacity to suppress the T-cell response through the production of immunoregulatory cytokines such as transforming growth factor (TGF)-β and IL-10 or by cell-to-cell interaction.[8, 9]

The key to a healthy immune system is its remarkable ability to distinguish between the body's own cells, recognized as ‘self’, and foreign cells, or ‘non-self’. Consequently, mammalian pregnancy constitutes a distinctive situation in which sophisticated immunoregulatory mechanisms are required to provide tolerance toward a genetically foreign conceptus, while at the same time allowing effective immunity to protect the mother from infections.[10] Among several explanations for the acceptance of the fetus, the one that suggests that the maternal immune system is suppressed or modified has been the subject of many studies. In agreement, several reports have demonstrated that during the normal pregnancy, a state of systemic suppression of the maternal immune system seems to be present.[11-13] However, except for certain pathogens with defined predilection for prenatal infection, in general pregnant women are not significantly more susceptible to infections than non-pregnant.[10, 14, 15]

Some years ago, Wegmann et al.[16] proposed that normal pregnancy is characterized by a lack of strong maternal, cell-mediated, antifetal immunity (Th1-type reactivity) and that instead, a dominant humoral immune response is prevalent (Th2-type reactivity). In agreement, several reports led to define the pregnancy as a Th2 or anti-inflammatory condition in which a poor pregnancy outcome may be associated with an increase in Th1-type response and a concomitant decrease in Th2-type response. Accordingly, predominant Th1-type immunity has been observed in recurrent spontaneous abortion and in pre-eclampsia.[17-19] However, predominant Th2-type immunity is also reported in recurrent pregnancy loss and, in humans, augmented Th1-type immunity or suppressed Th1-type immunity in the endometrium is observed in repeated implantation failure.[20-23] Therefore, an adequate balance for Th1/Th2 immunity with slight shift to Th2-type immunity may be suitable for the maintenance of pregnancy.

Recently, the Th1/Th2 paradigm in pregnancy has been redefined to include Th17 and Treg cells in view of the facts that these two populations are present in the decidua. Th17 response is known to play a pathogenic role in autoimmune diseases and in tissue rejection and thus may be harmful to the maintenance of pregnancy.[5, 6] Th17 cells and the expression of Th17-related factors (IL-17, IL-23, and RORγc) have been found to be increased in deciduas from unexplained inevitable recurrent spontaneous abortion patients; however, because Th17 increase was not observed in the decidua of abortion cases that did not show vaginal bleeding or cervical deletion, it is unclear whether the increased Th17 cells are a primary cause of merely a downstream consequence of fetal loss.[24, 25] On the other hand, Saito et al.[26] have reported that the frequency of Th17 in the decidua is significantly higher compared to that in peripheral blood and they suggest that decidual Th17 cells might be playing a role in the protective immune response against extracellular microbes, considering that the uterine cavity is not completely sterile.

Inflammation is necessary for successful implantation, but exacerbated inflammation is harmful to the pregnancy. Treg cells resident in decidua, peripheral blood, and lymph nodes are increased in mice and pregnant women, and there are evidences that fetus-specific Treg cells migrate from peripheral blood to the decidua in human pregnancy.[27-31] In addition, antibody-mediated depletion of CD25+ cells on the day or 2.5 days after mating of allogeneic, but not syngeneic, mice results in severe impairment of implantation.[30] These results suggest that Treg cells are essential for inducing immunological tolerance, and therefore, it can be speculated that decreased Treg cells might induce implantation failure, resulting in unexplained infertility or miscarriage. In agreement, it was observed that infertility, spontaneous abortion, pre-eclampsia, and recurrent spontaneous miscarriage cases are associated with decreased number of peripheral and decidual Treg cells and reduced immunosuppressive activity of Treg.[32-36] Also, it was recently demonstrated that during allogeneic pregnancy, the extrathymic generation of inducible or peripheral Treg (iTreg or pTreg) cells and their accumulation in the placenta play an important role by preventing embryo resorption and associated defective spiral artery remodeling.[37] Recent data show the reciprocal development pathways between Th17/Th1 subset and Th17/Treg subsets.[38] Thus, it is possible that placental cytokine milieu in addition to hormones and placental-derived factors be responsible for the development and maintenance of a non-pathogenic T-cell response compatible with a successful pregnancy.[36, 39-43]

Some years ago, Sacks et al.[44] proposed that soluble placental products released directly into the maternal circulation can generate specific pregnancy signals through interaction with the innate immune system. Thus, the innate immunity might be able to distinguish the pregnant from the non-pregnant state producing a signal, the so-called signal P, that modulates the lymphocyte response to alloantigen stimulation. In line with this hypothesis, several soluble factors and cells of placental origin have been demonstrated to be important to modulate the mothers’ T-cell response and thereby would contribute to marshaling the maternal immune system to support pregnancy.[40, 43, 45-47] In this review, we summarize current knowledge concerning the contribution of pregnancy-specific glycoprotein 1a (PSG1a), a representative member of the main glycoprotein family secreted by placental trophoblast, to modulate the maternal innate and adaptive immune response in order to assure a successful pregnancy.

Pregnancy-specific glycoproteins

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pregnancy-specific glycoproteins
  5. Effect of in vivo expression of PSG1a on the adaptive T-cell response
  6. PSGs modulate the immune system through their interaction with professional antigen-presenting cells
  7. PSG1a modulates the metabolism and cytokine secretion by monocyte/macrophage (MΦ) populations
  8. PSG1a targets DCs to differentiate into a subset with a unique phenotype and function
  9. Conclusions
  10. References

PSG1a belongs to the human PSG family, which is part of the immunoglobulin gene superfamily. PSGs are glycoproteins mainly synthesized by the placenta. Mature PSG proteins have molecular weights of 72, 64, and 54 kDa with about 30% of carbohydrates incorporated by N-glycosylation.[48] They represent early biochemical marker of syncytiotrophoblast formation and are the major group of secreted proteins found in maternal serum at the end of normal gestation.[49, 50]

The clinical relevance of this group of proteins has been suggested many years ago. Indeed, spontaneous abortion, pre-eclampsia, intrauterine growth retardation, small-for-gestational-age fetuses, and preterm delivery have been linked to low PSG levels in maternal circulation.[51-54]

PSG genes have been identified in non-human primates, rats, and mice; however, no unequivocal orthologous genes can be assigned.[55] In the human genome, there are 11 PSG genes with about 90% nucleotide sequence identity clustered within 700 kilobases on chromosome 19q13.2.[56] All PSG family members possess a similar gene organization. They code for a leader peptide (L) and an N-terminal domain homologous to the immunoglobulin variable domain. Depending on the gene, this domain is followed by up to three immunoglobulin C2-like domains (A and B) and a short variable carboxy-terminal tail (C). Alternative splicing may lead to different PSG transcript (Fig. 1). PSG1a, also named PSG1-4C1 splice variant, has the most frequent (LN-A1-A2-B2-C) arrangement with a C1-terminal tail.[57] PSG transcripts isolated from human placenta cDNA libraries support that all PSG genes are expressed. In addition, transcript-specific PCR analysis suggests that the whole PSG locus is activated in cytotrophoblast that differentiates into the syncytium pathway, although reaching different mRNA abundance levels.[49] It has been reported that in humans, PSGs are produced by the syncytiotrophoblast starting as early as about the time of implantation.[58] Their biosynthesis is regulated mainly at the transcriptional level and markedly increased during syncytiotrophoblast differentiation.[49, 59]

image

Figure 1. Schematic representation of pregnancy-specific glycoprotein genes and transcripts. (a) Exon arrangements represented by boxes shaded: cyan for leader (L) peptides; pink for N-terminal IgV-like domain (N); orange for IgC-like domain, A1 subset (A1); blue for IgC-like domain, A2 subset (A2); red for IgC-like domain, B subset (B); gray for hydrophilic tail, carboxy-terminal domain (C). (b) Known transcripts for each gene.

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Although their functions have not been fully established, several lines of evidence strongly suggest they are essential for the maintenance of a normal pregnancy. A few years after their identification, they were suspected of having a crucial role in modulating the maternal immune system although little is currently known about whether all members of this family of proteins have the same function and bind to the same receptor.[60, 61] Thus, several authors reported that placental-derived PSG proteins, which contained a mixture of the PSG family members, suppress mixed lymphocyte reaction and T-cell activation by mitogens.[62, 63] In contrast, Arnold et al.[51] found no effects on T-cell proliferation using recombinant human PSG1 or PSG11 molecules obtained in insect cells (which produce N-glycosylated proteins that may not be identical to those obtained using mammalian cells).[64] However, PSG protein participation in immune modulation and T-cell function is reinforced by the fact that high PSG levels are correlated with improved symptoms of rheumatoid arthritis and multiple sclerosis.[65, 66]

Years ago, it was reported that a peptide derived from human PSG 11 binds to a human monocyte receptor and to the cell surface of promonocyte lineage, but not to T or B cells.[67] In that report, it was demonstrated that the RGD motif present in the N-terminal domain of PSG11 is important for the binding of purified placental PSG to receptors present on activated human mononuclear cells.[67] More recently, it has been described that murine PSG17 and 19 bind to the tetraspanin CD9 on murine Mo and that the addition of carbohydrates is essential for PSG–receptor interaction.[68, 69] In contrast, human PSG1 and murine PSG22 and 23 did not bind to human or murine CD9 and bind to cell surface proteoglycans, while murine PSG17 is able to bind both proteoglycans and CD9.[68, 70, 71] Together, the results indicate that some members of PSG family have receptors on professional APCs and would have the ability to modulate the activity and function of these cells as will be described below.

Recently, another functions beyond to modulate the maternal immune system have been reported for these proteins. For instance, murine PSG22 and PSG23 are involved in placental angiogenesis because of their capacity to induce the secretion of TGF-β, an anti-inflammatory cytokine that also works as pro-angiogenic factor, in addition to induce VEGF by MΦ, DC, and endothelial cells.[72-74] In addition, we have observed that human PSG1a promotes IL-6, TGF-β, and VEGF secretion by JEG-3 cells (CC Motran and FF Martinez, unpublished data) and Dveksler's group has recently demonstrated that PSG1 induces endothelial tubulogenesis through interaction with cell surface proteoglycans.[70] Therefore, together these reports indicate that members of human and rodent PSG families have conserved functions that include their ability to modulate the immune system and to participate in the trophoblast-mediated vascular remodeling, both conditions that contribute to the establishment of a successful pregnancy.

In order to investigate the role of human PSG1a in the modulation of the immune system, we have used recombinant PSG1a obtained in mammalian cells using a vaccinia (Vac)-based expression vector harboring the complete open reading frame (ORF) of PSG1a cDNA. Thus, like the placental PSG, the recombinant molecule is synthesized and processed by human or mouse cells in culture to be secreted as a glycoprotein containing roughly 30% of its molecular mass of carbohydrates as was already reported.[48, 75, 76] In addition, recombinant PSG1a interacted with the Con A lectin, and the binding was inhibited by mannose analogs (α-methyl d-mannoside), a feature that is shared with the placental PSG.[59, 76]

Effect of in vivo expression of PSG1a on the adaptive T-cell response

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pregnancy-specific glycoproteins
  5. Effect of in vivo expression of PSG1a on the adaptive T-cell response
  6. PSGs modulate the immune system through their interaction with professional antigen-presenting cells
  7. PSG1a modulates the metabolism and cytokine secretion by monocyte/macrophage (MΦ) populations
  8. PSG1a targets DCs to differentiate into a subset with a unique phenotype and function
  9. Conclusions
  10. References

Some years ago, we have reported that in vivo expression of PSG1a before immunization with OVA in complete Freund's adjuvant favors the Th2-type response against OVA.[77] In this regard, it is important to remark the major role of circulating PSG1a in the decision process to mount a Th2-type immune response, because both adjuvants, CFA and vaccinia virus, used in that experimental system are strong Th1-type response inductors.[78, 79]

Recently, in order to investigate whether in vivo circulating PSG1a is able to modulate the Ag-specific T-cell response during an infection, the infection with Listeria monocytogenes, a facultative intracellular bacterium able to induce a strong protective Th1 response, was used as a model.[80] DO11.10 transgenic mice that were injected with a Vac-PSG1a were infected with L. monocytogenes expressing soluble OVA (rLm-OVA) to allow the detection of Ag-specific T-cell responses. In addition, to determine whether the PSG1a-induced T-cell response compromises the protective immunity to L. monocytogenes infection, mice that had been injected with Vac-PSG1a were primed with rLm-OVA and then challenged with higher Lm-OVA doses.

We observed that the infection with rLm-OVA in the context of circulating PSG1a (in vivo expression of PSG1a) promotes the expansion of Ag-specific IL-17-, IL-4-, and IL-10-secreting cells that are as able as the known effective Th1 response to protect against L. monocytogenes infection.[81] Interestingly, although it has been clearly demonstrated that during the acute phase of L. monocytogenes infection occurs the priming and expansion of Ag-specific effector T cells without changes in the number of Ag-specific Treg cells,[82] in vivo expression of PSG1a induced a similar growth of OVA-specific T cells, but concomitantly significantly expanded the percentage and absolute number of OVA-specific Foxp3CD25+ Treg cells.[81]

In those experiments, the Ag-specific CD4IL-17+ cells are in spleen from Vac-PSG1a-treated mice that were infected with L. monocytogenes. However, it is possible that during pregnancy, the Th17-mediated response might be restricted to the decidua, as suggested by the report showing that decidual formation prevents the DC stationed at the maternal/fetal interface from migrating to the lymphatic vessels of the uterus, and the fact that the frequency of Th17 cells in CD4+ T cells during all stages of pregnancy period is similar to that in non-pregnant women while being significantly higher in the decidua compared to that in peripheral blood.[26, 83] The recent reports showing that IL-17 increases progesterone secretion by the JEG-3 human choriocarcinoma cell line and induces the invasive capacity of these cells, together with those showing the ability of IL-17 to promote angiogenesis and tumor growth, suggest a role of IL-17 in the decidualization process.[84-86] Accordingly, we have observed that human IL-17 promotes VEGF secretion by JEG-3 cells through IL-6 signaling pathway (CC Motran and FF Martinez, unpublished data). Therefore, a population of Th17 cells in the decidua, tightly regulated by the presence of Treg cells and a milieu of cytokines containing IL-10, TGF-β, and/or IL-6 (that abrogate the Th17 pathogenic phenotype),[87, 88] but not IL-23, would have a beneficial rather than detrimental role during pregnancy.

PSGs modulate the immune system through their interaction with professional antigen-presenting cells

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pregnancy-specific glycoproteins
  5. Effect of in vivo expression of PSG1a on the adaptive T-cell response
  6. PSGs modulate the immune system through their interaction with professional antigen-presenting cells
  7. PSG1a modulates the metabolism and cytokine secretion by monocyte/macrophage (MΦ) populations
  8. PSG1a targets DCs to differentiate into a subset with a unique phenotype and function
  9. Conclusions
  10. References

During the last years, several groups have studied the effects of some variants of PSGs on immune system cells. To this end, placental-derived PSG, which contained a mixture of the PSG family members and recombinant PSGs expressed in insect or mammalian cells, were used obtaining similar results: PSGs are able to induce the secretion of immunomodulatory products by different types of cells such as monocytes, MΦ, DCs, endothelial cells, and trophoblast-derived cells.[51, 69, 72, 77, 81, 89-91] In addition, it was observed that murine PSGs mimic the biological effects of human PSGs inducing cytokine expression in human MΦ, and human PSGs induce the secretion of anti-inflammatory cytokines by human and murine MΦ.[90, 91] In contrast, none of the groups have reported direct effect of any of these glycoproteins on T or B cells, suggesting that PSGs might modulate the adaptive immune response through its interaction with cells other than T or B cells.[67, 75]

PSG1a modulates the metabolism and cytokine secretion by monocyte/macrophage (MΦ) populations

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pregnancy-specific glycoproteins
  5. Effect of in vivo expression of PSG1a on the adaptive T-cell response
  6. PSGs modulate the immune system through their interaction with professional antigen-presenting cells
  7. PSG1a modulates the metabolism and cytokine secretion by monocyte/macrophage (MΦ) populations
  8. PSG1a targets DCs to differentiate into a subset with a unique phenotype and function
  9. Conclusions
  10. References

MΦ populations, in addition to having a role in innate immunity, participate as effector cells in adaptive immune responses. Two different subsets of MΦ had been described. Classically activated MΦ occur in a type I cytokine environment (IFN-γ and TNF) and are inhibited by type II cytokines (IL-4, IL-10, and IL-13). They have cytotoxic and antimicrobial function, mainly based on their ability to secrete nitric oxide (NO).[92] In contrast, anti-inflammatory agents, such as IL-4, IL-10, IL-13, TGF-β, and glucocorticoids or Treg cells, induce alternative activation in MΦ, resulting in increased arginase activity (that competes with inducible NO synthase (iNOS) for its substrate, L-arginine) and enhanced expression of innate immunity receptors with broad specificity for foreign antigens (e.g., MΦ mannose receptor, scavenger receptor, and CD163).[92-94] IL-4/IL-13- and IL-10-induced MΦ are called alternatively activated MΦ (AAM), or more precisely wound-healing and regulatory MΦ, respectively.[95, 96]

AAM secrete anti-inflammatory molecules such as IL-10 and TGF-β and seem to be the first defense line cell that is not dependent on a strong Th1-mediated immune response to perform their function. In healthy organisms, these AAM are preferentially found in normal placenta and lung.[97] In addition, it has been proposed that AAM are able to induce differentiation of naïve T cells into antigen-specific Th2 cells.[98, 99] Moreover, although the contribution of Th17 cell-associated cytokines to MΦ biology is unclear, AAM have been recently associated with increased percentages of IL-17-producing cells in patients with sepsis, and the mannose receptor has been shown to be crucial for the induction of IL-17 by Candida albicans.[100, 101]

The cytokine milieu generated during pregnancy suggests the presence of AAM, whereas the presence of Th1 cytokines and classically activated MΦ is frequently associated with fetal loss.[17] Accordingly, we demonstrated that human PSG1a induces alternative activation in human peripheral blood monocytes and in human and murine monocyte cell lines because it up-regulates the arginase activity and inhibits the NO production in monocytes activated by lipopolysaccharides (LPS).[75] Moreover, in vivo expression of PSG1a by the treatment of mice with Vac-PSG1a induces alternative activation of spleen (SpMΦ) and peritoneal MΦ (PMΦ).[77]

It has been reported that human (PSG1, PSG6, the N-terminal domain of PSG6, PSG11, and its N-terminal domain containing the RGD peptide) as well as murine PSGs (PSG17 and PSG18) induce the secretion of IL-10, IL-6, and TGF-β1 in MΦ.[51, 89-91] In addition, in vivo expression of PSG1a induces PMΦ that produce, spontaneously in culture or after stimulus with LPS, high levels of TGF-β.[77] In addition, both PMΦ and SpMΦ from Vac-PSG1a-treated mice produce higher levels of IL-10 after LPS activation.[77] Together, these findings agree with the ability of different PSGs to induce an alternative phenotype in MΦ characterized by increased arginase activity and the ability to secrete the anti-inflammatory cytokines IL-10 and TGF-β. In addition, our results showing that PSG1a induces iNOS down-regulation and arginase up-regulation in monocytes stimulated by LPS suggest that the presence of PSG1a at the site of MΦ activation could induce a MΦ metabolic pathway deviation toward the alternatively activated one with the consequent enhancement of its capacity for antigen presentation.[92]

PSG1a is able to modulate the maternal T-cell immune response, acting as an important accessory cell–dependent T-cell suppressor factor because of its ability to inhibit the anti-CD3- or PHA-induced proliferation of human peripheral blood mononuclear cells.[75] In our experimental model, PMΦ from Vac-PSG1a-treated mice can produce PSG1a and profoundly inhibit the mitogen-induced proliferation of naïve T cells promoting the secretion of Th2-type cytokines (IL-5 and IL-4) and inhibiting the production of IL-2 and IFN-γ by cell-to-cell contact.[77] In contrast, SpMΦ from Vac-PSG1a-treated mice that do not produce PSG1a and are possibly targeted by circulating recPSG1a inhibit the mitogen-induced proliferation of naive T cells and induce Th2-type cytokine secretion by an IL-10-dependent mechanism.[77] Alternatively, activated PMΦ with similar functions have been reported in chronic nematode infections, where they appear to play a role in inducing Th2 and Treg differentiation.[102, 103]

The fact that PSG1a inhibits the T-cell proliferative response in accessory cell–dependent T-cell proliferation assays (as allo-mixed lymphocyte reactions, PHA-, and anti-CD3 stimulation) while highly purified T cells keep their ability to respond to MΦ-independent stimulus (such as anti-CD3 plus anti-CD28) suggests that PSG1a has not a direct effect on T lymphocytes.[75]

PSG1a targets DCs to differentiate into a subset with a unique phenotype and function

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pregnancy-specific glycoproteins
  5. Effect of in vivo expression of PSG1a on the adaptive T-cell response
  6. PSGs modulate the immune system through their interaction with professional antigen-presenting cells
  7. PSG1a modulates the metabolism and cytokine secretion by monocyte/macrophage (MΦ) populations
  8. PSG1a targets DCs to differentiate into a subset with a unique phenotype and function
  9. Conclusions
  10. References

In virtue of their plasticity and central role in orchestrating immunity and tolerance, DCs appear as candidates, among the decidual APC populations, to promote the appropriate immune response in order to support pregnancy.[104] Recent reports show the important role of uterine DCs for successful implantation.[105, 106] Thus, the number of uterine DCs increases at the implantation period, and depletion of DCs impairs uterine NK cell maturation, tissue remodeling, and angiogenesis.[105, 106] Moreover, evidence for the regulatory role of uterine DC cells at the fetal–maternal interface comes from studies in mice revealing that DCs present in uterus at the time of implantation belong to the myeloid lineage and exhibit a steady-state phenotype associated with the induction of tolerance.[107, 108]

The DC-derived factors that determine the outcome of DC–T-cell interactions are the Ag presentation levels, display of costimulatory molecules, and the presence of immunomodulatory factors such as cytokines. While increased Ag presentation levels and the expression of costimulatory molecules such as CD80, CD86, and CD40 on DC are crucial for the expansion of Ag-specific T cells, the expression of co-inhibitory 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.[109] In addition, stimuli that induce IL-12 promote IFN-γ-producing Th1 cells, stimuli that induce IL-10 and TGF-β favor Treg-cell differentiation, and stimuli that induce TGF-β and IL-6 promote a Th17 response in the mouse.[4, 110] In addition, IL-4 and IL-10 are both candidates for a Th2-driving signal from DCs; however, it has been demonstrated that both IL-4- and IL-10-deficient DCs can still drive Th2 responses.[111] Of note, the specific anatomical compartment where the immature DC (iDC) resides and encounters a maturation stimuli profoundly impacts the character of the immune response generated by the DC after it has migrated to the lymph nodes.[112, 113] Therefore, DCs can respond to pregnancy-specific signals, thus promoting the appropriate immune response of the mother and consequently the pregnancy outcome.

We used murine bone marrow–derived DCs to investigate the ability of PSG1a to modulate DC cytokine production, the expression of costimulatory molecules, and the T-cell-polarizing function and observed that iDCs treated with PSG1a differentiate into a subset with a unique phenotype and function. PSG1a-treated DCs present a semimature phenotype showing low surface CD40, ICAM-1, and MHC class II expression and the ability to secrete IL-6 and TGF-β. Treatment with PSG1a also affects the maturation of DCs, preventing the up-regulation of some costimulatory molecules and inducing the expression of PD-L1 and the secretion of TGF-β or IL-10 in response to TLR or CD40 ligation.[81]

The PSG-induced secretion of IL-6 and TGF-β has previously been reported in different cell types for human PSG1 and some murine PSGs.[89, 90] Taking into account the known roles of TGF-β and IL-6 in implantation, trophoblast differentiation and angiogenesis, and the direct participation of DCs in angiogenic responses, DCs accumulated in the uterus during the peri-implantation period may be targeted by PSG1a to provide DCs with a role in processes such as decidualization and placentation and the associated vascular adaptations.[107, 114] In addition, the up-regulation of PD-L1 expression on PSG1a-treated DC after TLR or CD40 ligation is particularly interesting because the syncytiotrophoblast expresses TLR, constitutively expresses PD-L1, and the loss of PD-1:PD-L1 signaling has been reported to impair fetomaternal tolerance.[115-117]

Moreover, in agreement with the reported expression of IL-10 by uterine DC, it also was reported that some PSGs can also induce IL-10 and TGF-β secretion.[89, 90, 108] In addition, SpMΦ from Vac-PSG1a-treated mice drive Th2 differentiation by an IL-10-dependent mechanism.[77] In our experimental setting, DCs treated with PSG1a secrete IL-10 only after the activation with anti-CD40 (treatment that mimics their interaction with T cells).

Interestingly, the PSG1a-treated DCs are able to activate Ag-specific T cells and to drive the acquisition of mixed phenotypes of Th2-type-/IL-17-secreting cells and Treg cells when they are pulsed with OVA peptide and used both in vitro to stimulate OVA-specific naïve T cells (from DO11.10 mice) and in vivo to immunize DO11.10 mice.[81] Interestingly, these data provide the first evidence for the existence of placental products able to activate DC to promote IL-17-producing cells.[81]

PSG1a-treated DC primes CD4+ T cells to produce IL-4 by a mechanism that involved IL-6 and IL-10 (as we demonstrated for SpMΦ targeted in vivo by PSG1a).[77] Moreover, the priming for Treg cells and IL-17-producing cells involves IL-6, TGF-β, PD-L1 and IL-10 signaling with IL-6, TGF-β, and PD-L1 signaling promoting both cell populations and IL-10 signaling partially suppressing the IL-17 secretion.[81] Recently, it has been demonstrated the key role of PD-L1 in promoting inducible Treg-cell development and function, with PD-L1 and TGF-β having synergistic roles, while PD-L1-PD-1 signaling is able to negatively regulate IL-17 differentiation.[118-120] On the other hand, IL-10 signaling can directly suppress Th17 cells.[87, 88]

IL-6, a cytokine produced by endometrial epithelium and stromal cells at the time of implantation,[121] is able to suppress IL-12-mediated T-cell polarization and direct Th2 differentiation of naïve T cells into IL-4-secreting cells.[122] In addition, IL-6 is a key cytokine that in the presence of TGF-β blocks the development of Treg cells and induces the differentiation of Th17 cells.[4, 5, 110] However, IL-6 neutralization in the PSG1a-treated DC–T cell co-cultures induces a significant decrease in Treg cells as well as IL-17 and IL-4 production, indicating that the ability of PSG1a-treated DCs to promote Treg, IL-17-, and IL-4-secreting cells relies on their capacity to produce IL-6.[81] Thus, IL-6 may be a ‘signal P’ induced by PSG1a able to modulate the phenotype and consequently the function of DCs. In agreement with this IL-6-dependent DC phenotype, a new type of tolerogenic DCs that are induced by activation with TLR2 or TLR4 ligands at low concentrations and including an autocrine/paracrine loop via IL-6 have been recently described.[123] This particular DC phenotype, like PSG1a-treated DC, shows a semimature phenotype and is resistant to TLR ligand-induced maturation.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pregnancy-specific glycoproteins
  5. Effect of in vivo expression of PSG1a on the adaptive T-cell response
  6. PSGs modulate the immune system through their interaction with professional antigen-presenting cells
  7. PSG1a modulates the metabolism and cytokine secretion by monocyte/macrophage (MΦ) populations
  8. PSG1a targets DCs to differentiate into a subset with a unique phenotype and function
  9. Conclusions
  10. References

These findings demonstrated that PSGs may have a ‘signal P’-inductor role during pregnancy, thus modulating the activation of the innate immune system and actively contributing to the T-cell shift of the maternal cell immunity toward a less harmful phenotype (Fig. 2).

image

Figure 2. A model for PSG1a modulation of innate and adaptive immune response and angiogenesis. PSG1a secreted by syncytiotrophoblast cells targets dendritic cells to differentiate into a subset with a unique phenotype and function able to activate Ag-specific T cells and drive the acquisition of mixed phenotypes of Th2-type-/IL-17-secreting cells and Treg cells through the expression of PD-L1 and the secretion of IL-6, TGF-β, and IL-10. PSG1a also induces an alternative phenotype in MΦ characterized by increased arginase activity and the ability to drive Th2-cell differentiation by an IL-10-dependent mechanism. In addition, PSGs as well as the PSG-induced cytokines (IL-6, TGF-β, IL-17) participate in the trophoblast-mediated vascular remodeling.

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During the early phase of pregnancy, a successful implantation occurs in a pro-inflammatory microenvironment and a Th1-type response, followed by a shift to a less deleterious response induced in part by some hormones and placental products. Therefore, this process could be seen as a ‘controlled inflammatory process’ that depends on the development of a Th1 response early modulated by PSG1a-targeted Mo and DC in order to restrict the initial Th1-effector response. Therefore, PSG1a and probably other PSG members may contribute to establishment of a uniquely regulated immune response in order to allow antimicrobial defense and tissue repair, while at the same time preventing damage to developing fetal organs or the triggering of preterm labor. In agreement with this hypothesis, pregnant women are generally not significantly more susceptible to infections than non-pregnant ones, with their adaptive immune system being prepared to mount an effective immune response to invading pathogens.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pregnancy-specific glycoproteins
  5. Effect of in vivo expression of PSG1a on the adaptive T-cell response
  6. PSGs modulate the immune system through their interaction with professional antigen-presenting cells
  7. PSG1a modulates the metabolism and cytokine secretion by monocyte/macrophage (MΦ) populations
  8. PSG1a targets DCs to differentiate into a subset with a unique phenotype and function
  9. Conclusions
  10. References