Placental Syncytin-2 Bearing Exosomes Promote Immune-tolerance Against Fetus During Pregnancy

Pregnancy is a unique event in which a foreign fetus survives to full term without apparent rejection by the mother’s immune system. Syncytin-2 is a protein derived from human endogenous retrovirus sequences and is an important player in the formation of the placenta. Syncytin-2 is incorporared on the surface of extracellular microvesicles, known as exosomes, which are released from the placenta. Previous studies have suggested that placenta exosomes had the intricate capacity to modulate function of various immune cell types, such as DCs and macrophages. In light of our recent results, we will determine if exosome-associated Syncytin-2 act upon immune cell function and if variation in their levels changes the immunosuppressive function of placenta-derived exosomes. Using Jurkat T cell, we demonstrated that synthetic peptide homologous to the sequence of syncytin-2 ISD dimer induced MAP kinases ERK1 and ERK 2 phosphorylation and inhibits TNF-a production after PMA- Ionomycin stimulation. We also showed that (Sync-2-ISD)₂ consistently suppressed IL-2, IL-5, IL-6 , IFN-g and TNF-a production in PBMC supernatant following stimulation with anti-CD3/CD28 or PMA- Ionomycin after incubation with (Sync-2-ISD)₂. We further demonstrated that placental Syncytin-2 bearing exosomes down-regulate TNF-a expression in Jurkat T cell and Th1 cytokines in PBMC. To confirm the involvement of Syncytin-2 in immune-regulation during pregnancy, we down regulated Syncytin-2 expression using small interfering RNA. Syncytin-2-depleted trophoblast exosomes were next incubated with PBMC and we demonstrated that syncytin 2 depletion prevent down-modulation of Th1 cytokines. In conclusion, our data suggested that syncytin-2, in particular (syncytin-2-ISD)₂ contributes greatly to prevent fetal allo-rejection by creating a "tolerant" microenvironment characterised by lowering Th1 cytokines.