Abstract
BackgroundT-helper polarization of naïve T cells is determined by a complex mechanism that involves many factors, eventually leading to activation of Th1, Th2, or Th17 responses or alternatively the generation of regulatory T cells. Placental Protein 14 (PP14) is a 28 kDa glycoprotein highly secreted in early pregnancy that is able to desensitize T cell receptor (TCR) signaling and modulate T cell activation.Methodology/Principal FindingsProlonged antigen-specific stimulation of T cells in the presence of PP14 resulted in an impaired secretion of IFN-γ, IL-5 and IL-17 upon restimulation, although the cells proliferated and expressed activation markers. Furthermore, the generation of regulatory CD4+CD25highFoxp3+ T cells was induced in the presence of PP14, in both antigen-specific as well as polyclonal stimulation. In accordance with previous reports, we found that the induction of FoxP3 expression by PP14 is accompanied by down regulation of the PI3K-mTOR signaling pathway.Conclusions/SignificanceThese data suggest that PP14 arrests T cells in a unique activated state that is not accompanied with the acquisition of effector function, together with promoting the generation of regulatory T cells. Taken together, our results may elucidate the role of PP14 in supporting immune tolerance in pregnancy by reducing T cell effector functions along with augmenting Treg differentiation.
Highlights
Placental Protein 14 (PP14) is a glycoprotein that belongs to the lipocalin superfamily, of which most members are extracellular proteins that function in transporting small hydrophobic ligands [1]
myelin basic protein (MBP)-specific T cells were generated in the presence or absence of PP14?Fcc1, as described in Materials and Methods, and restimulated with MBP, this time without PP14?Fcc1 in order to characterize the developmental fate of the cells
In order to better appreciate PP14’s impact on T cell activation and differentiation we compared its effects to that of transforming growth factor-b (TGF-b) by stimulating cells with MBP for 2 weeks in the presence of TGF-b followed by restimulation with MBP, this time in the absence of TGF-b
Summary
PP14 is a glycoprotein that belongs to the lipocalin superfamily, of which most members are extracellular proteins that function in transporting small hydrophobic ligands [1]. Amniotic PP14 is mainly synthesized in secretory endometrial glands and by gestational decidua where it is regulated by progesterone and it is the major secretory protein of human endometrial epithelial cells during the luteal phase and early pregnancy [3]. A correlation between low serum levels of PP14 and susceptible abortion has been recognized. This and other evidences suggest that high levels of PP14 may have an important role for establishment, maintenance, and progression of pregnancy and for early survival of the developing fetoplacental unit [4]. Placental Protein 14 (PP14) is a 28 kDa glycoprotein highly secreted in early pregnancy that is able to desensitize T cell receptor (TCR) signaling and modulate T cell activation
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