Abstract
NK cells present in the peripheral blood (PB) respond rapidly to pathogens or pathogen-infected cells by various means including cytotoxicity and release of cytokines and chemokines. In addition they modulate adaptive immunity via the interaction with dendritic cells. Decidual NK cells (dNK) are poorly cytotoxic in healthy pregnancy, both in humans and rodents, when compared to their PB counterparts. We will discuss recent findings that may contribute to answer the following questions: (i) Do dNK possess functional killing machinery in normal healthy pregnancy? (ii) If so, what are the regulatory mechanisms that negatively control this effector function? (iii) Have dNK from early pregnant uterus the intrinsic ability to kill pathogen-infected autologous maternal uterine cells and/or produce soluble factors that stimulate the anti-pathogen adaptive immune response? (iv) Do dNK undergo a receptor repertoire profile shift when they are in contact with pathogen-infected uterine cells? (v) Which pathogen-mediated signal(s) and molecular interactions subvert the inhibition of dNK cytolytic activity?
Highlights
During the last decade, an increasing body of data based on genetic and functional studies have provided compelling evidence that during early healthy pregnancy, decidual NK cells, the dominant lymphocyte population accumulated in the decidua basalis where the trophoblast cells infiltrate, exhibit unique functional and phenotypic characteristics [1,2,3,4,5]
We will discuss recent findings that may contribute to answer the following questions: (i) Do Decidual NK cells (dNK) possess functional killing machinery in normal healthy pregnancy? (ii) If so, what are the regulatory mechanisms that negatively control this effector function? (iii) Have dNK from early pregnant uterus the intrinsic ability to kill pathogen-infected autologous maternal uterine cells and/or produce soluble factors that stimulate the anti-pathogen adaptive immune response? (iv) Do dNK undergo a receptor repertoire profile shift when they are in contact with pathogen-infected uterine cells? (v) Which pathogen-mediated signal(s) and molecular interactions subvert the inhibition of dNK cytolytic activity?
WHICH PATHOGEN-MEDIATED SIGNAL(S) AND MOLECULAR INTERACTIONS SUBVERT THE INHIBITION OF DECIDUAL NK CELL CYTOLYTIC ACTIVITY? Using Fc-chimeric proteins, we found that human cytomegalovirus (hCMV) infection of decidual fibroblast modulated the expression of several NKR ligands: NKp30L and NKG2DL were significantly increased whereas NKp44L and NKp46L decreased [16]
Summary
An increasing body of data based on genetic and functional studies have provided compelling evidence that during early healthy pregnancy, decidual NK (dNK) cells, the dominant lymphocyte population accumulated in the decidua basalis where the trophoblast cells infiltrate, exhibit unique functional and phenotypic characteristics [1,2,3,4,5]. DNK promote vascular growth in the decidua through the production of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) [9, 13, 17,18,19] as well as of angiopoietin 1, angiopoietin 2, and TGF-β1 [15, 20] The release of these proangiogenic factors by dNK cells depends on the engagement of both NKp30 and NKp44 activating receptors by their specific ligands present on stromal decidual cells and extravillous trophoblast [17]. Migration of extravillous trophoblast cells results in the invasion of spiral arteries contributing to the uterine vascular remodeling crucial for the placental development and outcome of pregnancy [25] Such production of chemoattractants by dNK is due to the engagement of NKp30 and NKp44 by their specific ligands expressed by trophoblast and stromal decidual cells [17].
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