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

Modulation of the activation status of immune cell populations during pregnancy depends on placental villous cytotrophoblast (VCT) cells and the syncytiotrophoblast (STB) layer. Failure in the establishment of this immunoregulatory function leads to pregnancy complications. Our laboratory has been studying Syncytin-2 (Syn-2), an endogenous retroviral protein expressed in placenta and on the surface of placental exosomes. This protein plays an important role in STB formation through its fusogenic properties, but also possesses an active immunosuppressive domain (ISD). Considering that Syn-2 expression is importantly reduced in preeclamptic placentas, we were interested in addressing its possible immunoregulatory effects on T cells. Activated 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 phosphorylation levels of ERK1/2 MAP kinases was 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 Panel Multi-Analyte 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 severely reduced. 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 results suggest that Syn-2 could be an important immune regulator both locally and at the systemic level, via its association with placental exosomes.