Maternal obesity alters uterine NK activity through a functional KIR2DL1/S1 imbalance

Abstract

In pregnancy, uterine natural killer cells (uNK) play essential roles in coordinating uterine angiogenesis, blood vessel remodeling and promoting maternal tolerance to fetal tissue. Deviances from a normal uterine microenvironment are thought to modify uNK function(s) by limiting their ability to establish a healthy pregnancy. While maternal obesity has become a major health concern due to associations with adverse effects on fetal and maternal health, our understanding into how obesity contributes to poor pregnancy disorders is unknown. Given the importance of uNK in pregnancy, this study examines the impact of obesity on uNK function in women in early pregnancy. We identify that uNK from obese women show a greater propensity for cellular activation, but this difference does not translate into increased effector killing potential. Instead, uNK from obese women express an altered repertoire of natural killer receptors, including an imbalance in inhibitory KIR2DL1 and activating KIR2DS1 receptors that favors HLA-C2-directed uNK activation. Notably, we show that obesity-related KIR2DS1 skewing potentiates TNFα production upon receptor crosslinking. Together, these findings suggest that maternal obesity modifies uNK activity by altering the response toward HLA-C2 antigen and KIR2DL1/2DS1-controlled TNFα release. Furthermore, this work identifies alterations in uNK function resulting from maternal obesity that may impact early developmental processes important in pregnancy health.

Characterization of Surface Receptor Expression and Cytotoxicity of Human NK Cells and NK Cell Subsets in Overweight and Obese Humans

“…In accordance to previous studies, no significant differences in NKG2D expression were detected within total NK cells between the BMI groups (53,75,(84)(85)(86)(87). In contrast, other studies demonstrated altered NKG2D expression in obese individuals, although with conflicting results.…”

Regulation of Placental Extravillous Trophoblasts by the Maternal Uterine Environment

“…IL8, VEGF, placental growth factor (PGF) and CXCL10, also known as IP-10) ( 153 ). In uNK cells, expressing activating KIR2DS1 or KIR2DS4, HLA-C promotes uNK cell degranulation and secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor (TNF) ( 186 , 200 , 207 ). Production of these factors potentially impacts EVT biology (discussed below).…”

“…In contrast, others describe an elevated number of total uNK cells or of the CD56 + /CD16 + subset in PE ( 230 , 231 ). More recently, research has identified pre-existing health conditions of the mother that associate with low-grade inflammation, like obesity, that potentiate uNK cell activity and modify how uNK cells interact with fetal MHC ligand ( 207 ). However, although the in utero environment likely shapes uNK cell processes, to date, hard evidence showing that aberrantly activated uNK cells in humans directly target trophoblasts for killing has yet to be clearly demonstrated.…”

Maternal Obesity and the Uterine Immune Cell Landscape: The Shaping Role of Inflammation

“…Obesity dysregulates NK biology [201,[219][220][221][222], promoting a highly activated state [193,220,223]. Despite the critical importance of these cells in regulating placental establishment and development, only a few studies have examined the effect of maternal obesity on uNK activity [129,185,224]. There is conflicting evidence emerging from mouse models of DIO examining alterations on NKs within the utero-placental environment.…”