Myeloid-T cell proximity is prominent in healthy pregnancies with extreme fetal-maternal HLA incompatibility

Pregnancy requires local immune tolerization. Oocyte donation (OD) pregnancies, with extensive fetal-maternal human leukocyte antigen (HLA) mismatching, are at higher risk of pre-eclampsia. We hypothesize that immune adaptations are needed at the fetal-maternal interface to maintain healthy pregnancy despite high HLA dissimilarity. By multispectral imaging, myeloid cells constituted 65% of the decidual immune cells and encompassed 12 distinct clusters. Fully-allogeneic healthy OD pregnancies displayed a higher frequency of CD163⁺HLA-DR⁺ myeloid cells and FoxP3⁺CD4⁺ Tregs near CD4⁺ T cells compared to semi-allogeneic healthy pregnancies and pre-eclampsia, together with a Treg-reinforcing gene signature. Contrastingly, pre-eclampsia was characterized by enhanced inflammatory chemokine expression and oxidative-stress-gene imbalance. Pregnancy outcomes were unaffected by decidual pathology, maternal HLA antibodies, or fetal HLA-C/maternal KIR haplotypes. This study highlights the frequency, phenotypic diversity, and T cell proximity of decidual myeloid cells in OD pregnancies and suggests their immune regulatory effects to compensate for higher fetal-maternal HLA mismatch loads.