PSG9 Stimulates Increase in FoxP3+ Regulatory T-Cells through the TGF-β1 Pathway

Jones, Karlie; Ballesteros, Ángela; Mentink‐Kane, Margaret M.; Warren, James W.; Rattila, Shemona; Malech, Harry L.; Kang, Elizabeth M.; Dveksler, Gabriela S.

doi:10.1371/journal.pone.0158050

Cited by 30 publications

(38 citation statements)

References 53 publications

(58 reference statements)

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“…The effect of PSGs on lymphocyte proliferation is consistent with existing data [42,11]. According to these investigations, PSG1 and PSG9 suppressive effects are mediated through the TGF-β1 pathway [43,44]. This cytokine is secreted by many cells, including CD4 + Fig.…”

Section: Discussionsupporting

confidence: 87%

Effects of pregnancy-specific β-1-glycoprotein on the helper T-cell response

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Khramtsov

et al. 2019

ARCH BIOL SCI BELGRA

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Pregnancy-specific β-1-glycoproteins (PSGs) are capable of regulating innate and adaptive immunity. As fetal antigens circulate in the blood of pregnant women, it is of particular interest to reveal the effects of PSGs on the differentiation of memory T cells in the context of maternal-fetal tolerance formation. We studied if, native PSG preparation affects helper T-cell proliferation, the frequencies of CD4 + CD45R0 + , CD4 + CD45RA + , CD4 + CD45RA + CD45R0 + cells, naive CD45RA + CD45R0-CD62L + cells (NAIVE), central memory CD45RA-CD45R0 + CD62L + cells (TCM), effector memory helper T cells (CD45RA-CD45R0 + CD62L-(TEM) and CD45RA + CD45R0-CD62Lcells (TEMRA), together with IL-4 and IFN-γ production by all СD4 + T cells. The suppressive effect of PSG on helper T-cell proliferation was established. It was found that PSG does not influence the frequencies of CD45RA + and CD45R0 + cells, while it decreased the percentage of CD45RA + CD45R0 + cells. PSG increased the percentage of NAIVE cells in culture, and prevented the conversion of these cells into TEMRA, without affecting the levels of TCM and TEM. In addition, PSG lowered the amount of IL-4 and IFN-γ in the supernatants of helper T-cell cultures. As TEMRA exhibit cytotoxic activity that is unfavorable during pregnancy, the revealed PSG effects may play a fetoprotective role in vivo.

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Section: Discussionsupporting

confidence: 87%

Effects of pregnancy-specific β-1-glycoprotein on the helper T-cell response

Тимганова

Бочкова

Khramtsov

et al. 2019

ARCH BIOL SCI BELGRA

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“…Tumor-derived GM-CSF appears to drive the epithelial secretion of VEGF via an autocrine or paracrine mechanism [ 34 ]. Recently, PSG9 was proved to stimulate increase in FoxP3+ regulatory T cells through the TGF-β1 pathway [ 35 ]. It was not only consistence with our finding that PSG9 activated the TGF-β pathway, but also proved that PSG9 limited anti-tumor immunity and polarized microenvironment to a more pro-angiogenic microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Pregnancy-specific glycoprotein 9 (PSG9), a driver for colorectal cancer, enhances angiogenesis via activation of SMAD4

Yang

Tan

et al. 2016

Oncotarget

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PSG9 is a member of the pregnancy-specific glycoprotein (PSG) family and has been shown to contribute to the progression of colorectal cancer (CRC) and cancer-related angiogenesis. Here, we aim to investigate abnormal PSG9 levels in patients with CRC and to emphasize the role of PSG9 in driving tumorigenesis. Serum from 140 patients with CRC and 125 healthy controls as well as 74 paired tumors and adjacent normal tissue were used to determine PSG9 levels. We discovered that PSG9 was significantly increased in serum (P<0.001) and in tumor tissues (P<0.001) from patients with CRC. Interestingly, the increased PSG9 levels correlated with poor survival (P=0.009) and microvessel density (MVD) (P=0.034). The overexpression of PSG9 strongly promoted the proliferation and migration of HCT-116 and HT-29 cells. However, PSG9 depletion inhibited the proliferation of SW-480 cells. Using a human umbilical vein endothelial cell tube-forming assay, we found that PSG9 promoted angiogenesis. The overexpression of PSG9 also increased the growth of tumor xenografts in nude mice. Co-immunoprecipitation experiments revealed that PSG9 was bound to SMAD4. The PSG9/SMAD4 complex recruited cytoplasmic SMAD2/3 to form a complex, which enhanced SMAD4 nuclear retention. The PSG9 and SMAD4 complex activated the expression of multiple angiogenesis-related genes (included IGFBP-3, PDGF-AA, GM-CSF, and VEGFA). Together, our findings illustrate the innovative mechanism by which PSG9 drives the progression of CRC and tumor angiogenesis. This occurs via nuclear translocation of PSG9/SMAD4, which activates angiogenic cytokines. Therefore, our study may provide evidence for novel treatment strategies by targeting PSG9 in antiangiogenic cancer therapy.

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“…Cells were plated in 96-well plates at a concentration of 1 £ 10 5 cells/well and then activated with mouse CD3/CD28 T cell activator Dynabeads (Thermo Fisher Scientific). IL-2 secretion was examined as described previously [20].…”

Section: Cytokine and Chemokine Measurementsmentioning

confidence: 99%

Recombinant Pregnancy-Specific Glycoprotein 1 Has a Protective Role in a Murine Model of Acute Graft-versus-Host Disease

Jones

Bryant

Luo

et al. 2019

Biology of Blood and Marrow Transplantation

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Acute graft-versus-host disease (aGVHD) is an immune-mediated reaction that can occur after hematopoietic stem cell transplantation in which donor T cells recognize the host antigens as foreign, destroying host tissues. Establishment of a tolerogenic immune environment while preserving the immune response to infectious agents is required for successful bone marrow transplantation. Pregnancy-specific glycoprotein 1 (PSG1), which is secreted by the human placenta into the maternal circulation throughout pregnancy, likely plays a role in maintaining immunotolerance to prevent rejection of the fetus by the maternal immune system. We have previously shown that PSG1 activates the latent form of transforming growth factor b1 (TGF-b), a cytokine essential for the differentiation of tolerance-inducing CD4 + FoxP3 + regulatory T cells (Tregs). Consistent with this observation, treatment of na€ ıve murine T cells with PSG1 resulted in a significant increase in FoxP3 + cells that was blocked by a TGF-b receptor I inhibitor. We also show here that PSG1 can increase the availability of active TGF-b in vivo. As the role of CD4 + FoxP3 + cells in the prevention of aGVHD is well established, we tested whether PSG1 has beneficial effects in a murine aGHVD transplantation model. PSG1-treated mice had reduced numbers of tissueinfiltrating inflammatory CD3 + T cells and had increased expression of FoxP3 in T cells compared with vehicletreated mice. In addition, administration of PSG1 significantly inhibited aGVHD-associated weight loss and mortality. On the other hand, administration of PSG1 was less effective in managing aGVHD in the presence of an alloimmune reaction against a malignancy in a graft-versus-leukemia experimental model. Combined, this data strongly suggests that PSG1 could be a promising treatment option for patients with aGVHD following bone marrow transplantation for a nonmalignant condition, such as an autoimmune disorder or a genetic immunodeficiency. Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation.

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PSG9 Stimulates Increase in FoxP3+ Regulatory T-Cells through the TGF-β1 Pathway

Cited by 30 publications

References 53 publications

Effects of pregnancy-specific β-1-glycoprotein on the helper T-cell response

Effects of pregnancy-specific β-1-glycoprotein on the helper T-cell response

Pregnancy-specific glycoprotein 9 (PSG9), a driver for colorectal cancer, enhances angiogenesis via activation of SMAD4

Recombinant Pregnancy-Specific Glycoprotein 1 Has a Protective Role in a Murine Model of Acute Graft-versus-Host Disease

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