Moriya Gamliel1, Debra S. Goldman-Wohl2, Ronit Haimov-Kochman2, Avraham Nahum2, Iris Eisenberg2, Hagai Amsalem2, Simcha Yagel2, Ofer Mandelboim1.
1Hebrew University Faculty of Medicine, Jerusalem, Israel, 2Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Introduction: Natural killer cells (NKs) are abundant in the human decidua, supporting development of the placental bed. The great obstetrical syndromes are often associated with inefficient placentation, particularly in first pregnancies. We hypothesized that NK cells remember pregnancy with enhanced response in growth factor secretion in subsequent pregnancies.
Materials and Methods: Characterization of decidual NKs (from elective pregnancy terminations) from primigravid (n=85) vs parous (n=248) women using cell surface markers (flow cytometry), transcriptome expression (RNA-seq), epigenetic signature (ATAC-seq, WGBS), growth factor secretion (ELISA), and functional assays (in vitro-aortic ring and in vivo- tumor growth mouse model). Additionally, endometrial and peripheral blood NK cells from nulligravidae and parous women were tested.
Results: We found an NK cell population unique to all multipara, unique to NK cells and independent of gestational week (6-14), maternal age (17-47) or gravidity (in parous women). These NK cells possess a novel transcriptome and epigenetic signature, and significantly high expression levels of activating receptors NKG2C and LILRB1. Ligand triggering of these receptors with addition of IL-15, led to increased secretion of VEGFa and IFNγ, with functionality in vascular budding and trophoblast-tumor growth assays. Furthermore, higher levels of NKG2C were observed in endometrial but not in peripheral blood NK cells of parous as compared to nulliparous women.
Conclusion: We propose that decidual NK cells, likely residing in the uterus between pregnancies, remember pregnancy, enhancing future pregnancies by secreting pro-angiogenic factors. These memory NK cells may yield insight with therapeutic potential for treating the “Great Obstetrical Syndromes.”