Mathematical modelling of Natural Killer Intracellular Mechanisms
Poster to be presented at HARMONY 2019 and Experimental Biology 2019.
Pregnancy success is critically dependent on remodelling of maternal uterine arteries (spiral arteries) by placental cells (trophoblasts). There is strong evidence that this process is modulated by immune cells, specifically uterine natural killer (uNK) cells. Natural killer (NK) cell action on aberrant cells by secretion of cytotoxins is locally inhibited during pregnancy to promote implantation. The mother’s ‘tolerant’ response to invading trophoblasts may be key to a successful pregnancy, but this immune tolerance is incompletely understood. We hypothesize that differential expression of key activation and inhibition receptors in uNK compared with peripheral natural killer cells (pNK) may play an important role in this process.
This study employs mathematical modelling to investigate the downstream effects of NK cells’ activation and inhibition receptors after stimulation by various levels of ligands. Our model is based on a comprehensive qualitative description of the intracellular signalling pathways leading to chemokine and cytotoxin release from pNKs obtained from the KEGG database (https://www.genome.jp/kegg-bin/show_pathway?hsa04650). From this qualitative description we built a novel quantitative model, reusing existing curated models where possible and implementing new models as needed. This approach was enabled through the availability of these models in standard formats in publicly accessible repositories. This is the first model to incorporate a comprehensive description of the pathways between activation and inhibition receptors and the secretion of IFNγ, TNFα and GM-CSF cytokines, which aims to predict pNK function with the necessary detail to match existing literature data.
We then used our model to investigate whether changes in relative receptor expression between pNK and uNK can be sufficient to change cell behaviour as expected in pregnancy. The model reveals the relative importance of different reactions for molecules in the NK intracellular pathways on secretion of IFNγ, TNFα and GM-CSF cytokines for both types of NK cells. This model provides important steps toward understanding how differential receptor expression between these two classes of NK cells impacts their function. In particular, we demonstrate model predictions of how the increased expression of receptors for human leukocyte antigens (HLA-C, -E, and -G) and decreased expression of receptors typically expressed by pNK (e.g. ITG, NKG2D and KIR3) contribute to altered cytokine secretion in uNKs. Ultimately, this new knowledge will help us to define the interaction between placental trophoblast and uNKs in humans.