Extracellular vesicles deliver feto-placental paternal antigens to maternal secondary lymphoid tissues for T cell recognition.

Abstract

Abstract Pregnancy constitutes an immunological paradox, where despite the competent maternal immune system, the semi-allogeneic fetus evades rejection. The mechanisms at the maternal-fetal interface and mother’s secondary lymphoid tissues (SLTs) that dodge the immunologic attack to the fetus, remain largely unknown. Passage of extracellular vesicles (EVs) is a mechanism of cell-to-cell communication that transfer antigens (Ags), regulatory mediators, and RNAs. Thus, we tested whether, similar to transplantation, feto-placental EVs could transport fetoplacental Ags via blood to maternal SLT immune cells, in this case in a tolerogenic fashion Results: In female BALB/c mice impregnated with mOVA C57Bl/6 (B6) males, the surrogate paternal Ag OVA accumulated on follicular dendritic cells (FDCs) in maternal SLTs (E17.5). In a mouse model in which EVs released by the fetoplacental unit are labelled with mNeonGreen linked to EV-CD81, mNeonGreen-CD81 was detected by microscopy in punctate areas on FDCs, conventional DCs, B cells, and macrophages in the mother’s spleen (E17.5). IP followed by western blot of EVs from cultures of trophoblast cells from BALB/c females impregnated with OVA B6 males, revealed OVA on the EVs. Administration of these EVs to non-pregnant females induced defective activation and proliferation of OVA-specific T cells in SLTs. In a human translational mouse model, iv injection of CM-DiI EVs from supernatant of primary human trophoblast cells were captured by B cells, macrophages, and cDCs of human origin in the spleen Conclusion: In the models tested, systemically released feto-placental EVs carry paternal/trophoblast Ags that reach the maternal SLTs, where the Ags are recognized by maternal T cells. NIH R01 AI148690.