Predicting the dialogue between placental and uterine immune cells in early human pregnancy

Supervised by: Dr. Roser Vento-Tormo (rv4@sanger.ac.uk) and Dr. Marta Shahbazi (mshahbazi@mrc-lmb.cam.ac.uk)

Project Title: Predicting the dialogue between placental and uterine immune cells in early human pregnancy

Project description 

Successful human pregnancy relies on proper formation of the placenta, a transient embryo-derived organ positioned at the interface between the mother and fetus. During placental development, specialised placental cells called trophoblasts invade the uterus and remodel its arteries, establishing maternal-fetal blood circulation by the end of the first trimester. The extent of trophoblast invasion therefore dictates pregnancy outcome, with abnormal invasion underpinning major gestational complications including pre-eclampsia, fetal growth restriction, and spontaneous miscarriage (1). Despite its critical role in maternal-fetal health, placentation remains understudied due to limited access to human tissue and the lack of suitable model organisms that recapitulate human-specific features of placental development.

Advances in single-cell genomics have transformed our ability to study complex tissues, especially those involved in reproduction (2). Using these approaches, our team has generated atlases of the uterus and its interactions with the placenta in early human pregnancy, resolving cell types, lineage commitment, and communication networks across time and space (3, 4). These atlases revealed a central role for maternal immune cells, particularly uterine natural killer cells (uNK), in regulating placentation. Constituting the most abundant immune cell type in the pregnant uterine lining, uNK cells produce chemokines that promote trophoblast invasion while expressing immunoregulatory molecules that prevent maternal rejection of the fetus. Our lab aims to dissect the mechanisms that maintain this precise balance and ultimately govern pregnancy success.

Trophoblast HLA-C and non-classical HLA-G are recognised by a specialised subset of uNK cells via their high expression of Killer-cell Immunoglobulin-like Receptors (KIRs) (3). Notably, the KIR genes and HLA-C locus are highly polymorphic: specific maternal KIR-fetal HLA-C combinations can elicit variable uNK responses, with certain pairings associated with an increased risk of pre-eclampsia (5). Comprehensive profiling of uNK-trophoblast interactions through KIR/HLA-C, alongside characterisation of uNK-derived cytokine effects on trophoblast invasion, is therefore essential to better understand immune-placental crosstalk in both healthy and diseased pregnancy.

However, exploring this dialogue has been challenging because current single-cell studies sample only a limited number of individuals, leaving KIR/HLA-C combinatorial diversity largely unexamined. Additionally, dissecting mechanistic causality requires perturbable models of the maternal-fetal interface that faithfully recapitulate maternal immune and fetal trophoblast cells.

This PhD Studentship aims to overcome these challenges through three objectives:

1. Establish and profile co-cultures of uNK cells and trophoblasts that capture diverse KIR/HLA-C combinations, generating a dictionary of uNK-placental cell interactions that link specific maternal-fetal genotype pairings to transcriptomic and cytokine profiles.
2. Predict the functional impacts of these interactions on trophoblast invasion by computationally reconstructing key signalling cascades and linking immune transcriptomes to cytokine secretion.
3. Validate these predictions via functional assays leveraging microfluidics, mass spectrometry, and targeted metabolomics to examine the effects of KIR/HLA-C interactions on trophoblast invasion and uNK cytotoxicity.

Overall, this project will elucidate the mechanisms by which maternal immune cells shape human placentation, establishing a foundation for identifying novel, non-hormonal therapeutic targets to improve pregnancy outcomes worldwide.

References

1. Brosens, I., Pijnenborg, R., Vercruysse, L. & Romero, R. The ‘Great Obstetrical Syndromes’ are associated with disorders of deep placentation. Am. J. Obstet. Gynecol. 204, 193–201 (2011).
2. Marečková, M., Massalha, H., Lorenzi, V. & Vento-Tormo, R. Mapping human reproduction with single-cell genomics. Annu. Rev. Genomics Hum. Genet. 23, 523–547 (2022).
3. Vento-Tormo, R. et al. Single-cell reconstruction of the early maternal-fetal interface in humans. Nature 563, 347–353 (2018).
4. Arutyunyan, A. et al. Spatial multiomics map of trophoblast development in early pregnancy. Nature 616, 143–151 (2023).
5. Huhn, O. et al. High-resolution genetic and phenotypic analysis of KIR2DL1 alleles and their association with pre-eclampsia. J. Immunol. 201, 2593–2601 (2018).

Candidate background requirements

• Experience with cell and/or organoid culture
• Programming skills, preferably in Python
• Background in bioengineering research, preferably with synthetic hydrogels or microfluidics