The frequencies of preeclampsia, fetal growth restriction, fetal demise, and low birthweight are lower in subsequent pregnancies. Enhanced maternal cardiovascular adaptation, shorter first and second stages of labor, and more robust lactation also have been observed in subsequent as compared with first pregnancies. We sought to investigate the cellular and molecular bases for better outcomes in subsequent pregnancies. Based on the knowledge that specialized immune cells at the maternal–fetal interface, decidual natural killer cells, promote development of the placental bed and conversion of the spiral arteries by secreting a myriad of angiogenic and growth factors, we asked whether decidual natural killer cells differ in subsequent as compared with first pregnancies. This idea stemmed from recent studies suggesting that natural killer cells, although part of the innate immune system, possess some features of adaptive immunity, including a certain type of immune cell memory, termed trained immunity. We found that decidual natural killer cells from parous women “remember pregnancy” and differ from decidual natural killer cells of primigravidae. Compared with the decidual natural killer cells of first pregnancy, these cells, that we termed pregnancy-trained decidual natural killer cells, express greater levels of the natural killer receptors NKG2C and leukocyte immunoglobulin-like receptor B1, which interact with ligands expressed on invasive trophoblasts. Furthermore, they secrete greater levels of several growth factors, including vascular endothelial growth factor α as well as interferon-γ, augmenting remodeling of the placental bed. We propose that this pregnancy-trained memory dwells in the epigenome, where memory of stimuli is known to persist even when the stimulus is no longer present. This epigenetic memory apparently resides in endometrial natural killer cells between pregnancies. We suggest that this trained memory, which we coined pregnancy-trained decidual natural killer cells, may be the missing link in the immune basis for enhanced subsequent pregnancy. Epigenetic memory (chromatin modification) also may afford a global explanation for additional findings of enhanced maternal cardiovascular adaptation, shorter first and second stages of labor, and more robust lactation. Understanding the molecular and cellular bases of improved outcomes of subsequent pregnancy may lead to the development of treatment modalities designed for women at high risk for pregnancy disorders originating at the maternal–fetal interface.
Bibliographical noteFunding Information:
The authors thank the past and present members of The Magda and Richard Hoffman Center for Human Placenta Research and the Mandelboim Laboratory for helpful insights and discussions. We thank Professor Ilana Ariel, Caryn Greenfield, and Galina Skarzinski, PhD, of the Department of Pathology, Hadassah-Hebrew University Medical Center, Mt. Scopus (I.A. G.S.) and Magda and Richard Hoffman Center for Human Placenta Research (C.G.), for Figure 2. We thank Sarah M. Cohen, MPH, of the Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Mt. Scopus, for preparing and modifying the figures and for expert editing of the manuscript.
© 2019 Elsevier Inc.
- DNA methylation
- NK cells
- decidual NK cells
- fetal growth restriction
- trained memory