Cross‐decoration of dendritic cells by non‐inherited maternal antigen‐containing extracellular vesicles: Potential mechanism for PD‐L1‐based tolerance in cord blood and organ transplantation

Exposure to non‐inherited maternal antigens (NIMA) during the fetal period induces lifelong split tolerance to grafts expressing these allo‐antigens. In adult mice, the production of extracellular vesicles (EVs) from maternal microchimeric cells causes cross‐decoration (XD) of offspring dendritic cells (DC) with NIMA and upregulation of PD‐L1, contributing to NIMA tolerance. To see how this may apply to humans, we tested NIMA acquisition by fetal DCS in human cord blood. The average percentage of NIMA‐XD among total DCs was 2.6% for myeloid and 4.5% for Plasmacytoid DC. These cells showed higher PD‐L1 expression than their non‐XD counterparts (mDC: p = .0016; pDC: p = .024). We detected CD9(+) EVs bearing NIMA and PD‐L1 in cord blood. To determine if this immune regulatory mechanism persists beyond the pregnancy, we analyzed NIMA‐expressing kidney and liver transplant recipients. We found donor antigen XD DCs in peripheral blood and graft‐infiltrating DCs. As in cord blood, the pattern of donor antigen expression was punctate, and PD‐L1 expression was upregulated, likely due to both protein and miRNA acquired from EV. Our findings support a mechanism for split tolerance to NIMAs that develops during pregnancy and is recapitulated in adult transplant recipients.