Postdoctoral Fellow University of Pittsburgh Baden, Pennsylvania, United States
Disclosure(s):
Juliana Powell, PhD: No financial relationships to disclose
Introduction/Rationale: Pregnancy constitutes an “immunological paradox,” where despite the competent maternal immune system, the semi-allogeneic fetus evades rejection. Mechanisms at the maternal-fetal interface and mother’s SLTs that dodge the immunologic attack to the fetus, remain unknown. Passage of small extracellular vesicles (EVs) is a mechanism of cell-to-cell communication that transfer Ags, regulatory mediators, and RNAs. Thus, akin to transplantation, fetoplacental-derived EVs transported via blood could represent a mechanism by which fetoplacental Ags and immune-regulatory mediators could be delivered to maternal SLT immune cells for recognition.
Methods: We tested whether fetoplacental EVs could transport paternal Ags to maternal SLTs and reprogram maternal APCs to induce tolerance.
Results: In a mouse model in which EVs released by the fetoplacental unit are labelled with red fluorochrome mScarlet linked to small EV-associated marker CD63, mScarlet-CD63 was detected by fluorescence microscopy in APCs in the maternal spleen. Immunoelectron microscopy revealed OVA on EVs. Administration of these trophoblast-derived EVs to virgin females induced defective activation and proliferation of OVA-specific CD4 (OT-II) and CD8 (OT-I) TCR transgenic T cells in the spleen. In Rab27a-/- mice in which vesicle release is deficient, OVA-specific OT-I proliferation is reduced. Trophoblast sEVs are taken up by different subsets of splenocytes. Paternal Ag, OVA, and fetoplacental EVs are retained in maternal tissues until at least post-partum (PP) day 30. Proteomics analysis revealed that mouse trophoblast sEVs were enriched in anti-inflammatory and immunosuppressive mediators.
Conclusion: Therefore, systemically released fetoplacental EVs carry paternal/trophoblast Ags and immunosuppressive cargo that reach the maternal APCs in the mother’s SLTs, where the Ags are presented in a manner that promote deficient activation of T cells as occurs during a normal pregnancy.
