'Natural killer' immune cells reveal factors for reproductive success

Immune cells known as natural killer (NK) cells are linked with pregnancy problems including pre-eclampsia and recurrent miscarriage. Collaborative research between scientists at the Babraham Institute and Centre for Trophoblast Research in Cambridge is illuminating the role that pregnancy-related NK cells play in moderating the biochemical interactions at the boundary between maternal tissues and the developing foetus.

Their findings, reported in November’s Journal of Immunology, reveal that uterine NK cells are ‘armed’ with specific receptors, enabling interaction with other molecules to ensure that the placenta develops normally and the pregnancy is successful.

Natural Killer (NK) cells, a type of white blood cell, defend us from tumours, viruses and other potential dangers. They sense their environment through a repertoire of surface proteins (receptors), which detect other immune molecules, those belonging to the Major Histocompatability Complex (MHC). This allows NK cells to distinguish ‘friend from foe’ and attack cells that have either lost self-MHC molecules or express a different set of MHC molecules.

A specialised set of NK cells accumulates in the uterus during each menstrual cycle and, if a fertilised embryo implants, their numbers rapidly swell at the maternal-foetal boundary. The role of these cells in pregnancy is enigmatic. Instead of the killing function normally associated with NK cells, in the uterus NK cells work in a different way; they are thought to make factors known as cytokines, which help to modify the maternal arteries supplying the developing foetus with the necessary blood, nutrients and oxygen. These dramatic tissue changes must be orchestrated in the context of the genetic diversity between the maternal immune cells and the paternal genes expressed on the developing placenta. Hostile interactions between maternal uterine NK cells and paternal MHC molecules are associated with an increased likelihood of abnormal pregnancies and recurrent miscarriage. However, the receptors enabling uterine NK cells to interact with MHC are only recently being uncovered. It is also unclear how maternal immune cells recognise paternal molecules in the unique micro-environment of the developing placenta, preventing an attack being mounted.

The Cambridge collaborators have identified the repertoire of activating and inhibitory receptors present on uterine NK cells and demonstrated that they are different from blood NK cells in terms of their adhesion, activation and MHC recognition capabilities.

“Not enough is known about these unique cells and their important role in pregnancy,” said Hakim Yadi, lead author and PhD student at the Babraham Institute. “This unprecedented and in-depth analysis of uterine killer cells is the necessary groundwork upon which we can build new knowledge. This will aid us in determining the factors that regulate reproductive success”.

The team’s analysis also revealed that uterine NK cells can be separated in two previously unappreciated subsets, opening up new questions related to their origin and functions, insights that will further understanding of the unique role of immune cells at the maternal-foetal interface.

This research was supported by the BBSRC, through a Babraham Institute Synergy Award to Drs. Francesco Colucci and Myriam Hemberger, an MRC Project Grant to Francesco Colucci and by the recently established Centre for Trophoblast Research at the University of Cambridge.

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