Exploring human uterine immune cell dynamics with a focus on natural killer cells and mait cells

The uterine immune system is crucial for the establishment of a healthy pregnancy and further development of the embryo. Although a lot is known about endometrial immune cell frequencies, phenotype, and function there are several aspects of the endometrial immune system that remain unknown. In this thesis, I explored several different aspects of the uterine immune system.

In paper I, we investigated the dynamics of endometrial mucosal associated invariant T cells (MAIT) cells in various reproductive states and assessed their ability to react to the sexually transmitted bacteria Neisseria gonorrhoeae. In addition, we examined the tissue-residency properties of endometrial MAIT cells using unique human samples obtained after uterus transplantation.

In paper II, we conducted a twin study to investigate what drives baseline differences in the endometrial immune system between healthy individuals. The results provide understanding of how the uterine immune cells respond to environmental factors and change through the course of a woman’s life. We found that there is more immune variation in immune cells of the endometrium compared to blood immune cells and that the differences are driven by distinct factors.

In paper III, we explored uterine NK (uNK) cell differentiation in relation to the endometrial regeneration occurring during the menstrual cycle and pregnancy. Our findings reveal that uNK cells differentiate continuously throughout the menstrual cycle, with a notable shift towards enhanced angiogenic function and immunomodulatory properties. This functional shift could potentially aid in spiral artery formation during early pregnancy.

In summary, this thesis provides valuable new insights into reproductive immunology and explains various aspects of the function of the uterine immune system.

LIST OF SCIENTIFIC PAPERS

I. Jonna Bister, Ylva Crona-Guterstam, Benedikt Strunz, Bogdan Dumitrescu, Karin Haij Bhattarai, Volkan Özenci, Mats Brännström, Martin A. Ivarsson, Sebastian Gidlöf, and Niklas K. Björkström. Human endometrial MAIT cells are transiently tissue resident and respond to Neisseria gonorrhoeae. Mucosal Immunology, 2021, vol.14 (2), pp. 357-365 https://doi.org/10.1038/s41385-020-0331-5

II. Jonna Bister, Iva Filipovic*, Dan Sun*, Ylva Crona-Guterstam, Martin Cornillet, Andrea Ponzetta, Jakob Michaëlsson, Sebastian Gidlöf, Martin A. Ivarsson, Benedikt Strunz, and Niklas K. Björkström. Tissue-specific nonheritable influences drive endometrial immune system variation. Science Immunology, 2024, vol. 9 (94), eadj7168 https://doi.org/10.1126/sciimmunol.adj7168

III. Benedikt Strunz, Jonna Bister, Russell S. Hamilton, Hanna Jönsson, Ylva Crona-Guterstam, Egle Kvedaraite, Iva Filipovic, Natalie Sleiers, Bogdan Dumitrescu, Danielle Friberg, Mats Brännström, Antonio Lentini, Björn Reinius, Martin Cornillet, Tim Willinger, Sebastian Gidlöf, Martin A. Ivarsson, and Niklas K. Björkström. Continuous human uterine NK cell differentiation in response to endometrial regeneration and pregnancy. Science Immunology, 2021, vol. 6 (56), eabb7800 https://doi.org/10.1126/sciimmunol.abb7800

*These authors contributed equally to the manuscript