Endogenous retrovirus encoded Syncytin-2 contributes to exosome-mediated immunosuppression of T cells. Biology of Reproduction,

Abstract

3AbstractModulation of the activation status of immune cell populations during pregnancydepends on placental villous cytotrophoblast (VCT)cellsand the syncytiotrophoblast (STB) layer. Failure in the establishment of this immunoregulatory functionleads to pregnancy complications. Our 5laboratory has been studying Syncytin-2 (Syn-2), an endogenous retroviral protein expressed in placentaand on the surface of placental exosomes. This protein plays an important role in STB formation through its fusogenic properties,but alsopossessesanactive immunosuppressive domain (ISD). Considering thatSyn-2 expression is importantly reduced in preeclamptic placentas, we were interested in addressing itspossible immunoregulatory effectson T cells.10Activated Jurkat T cells and peripheral blood mononuclear cells (PBMCs) were treated with monomeric or dimerized version of a control or a Syn-2 ISD peptide. Change in phosphorylationlevels of ERK1/2MAP kinaseswas selectively noted in Jurkat cells treated with the dimerized ISD peptide. Upon incubation with the dimerized Syn-2 ISD peptide, significant reduction in Th1 cytokine production was further demonstrated by ELISA and Human Th1/Th2 PanelMulti-15Analyte Flow Assay.To determine if exosome-associated Syn-2 could also have an immunosuppressive effect, placental exosomes were incubated with activated Jurkat T cells and PBMCs. Upon quantification of Th1 cytokines in the supernatants, T cell activation was severelyreduced. Interestingly, exosomes from Syn-2-silenced VCT incubated with PBMCS were less suppressive when compared to exosome derived from VCT transfected with control siRNA.Our 20results suggest that Syn-2 could be an important immune regulator both locally and at the systemic level, via its association with placental exosomes.