Increase in Tissue-Resident Natural Killer cells in Uterine Tissue in Preparation for and during Pregnancy

*Based On: Dorothy K. Sojka, Liping Yang, Beatrice Plougastel-Douglas, Darryl A. Higuchi, B. Anne Croy, Wayne M. Yokoyama. (2018). Cutting Edge: Local Proliferation of Uterine Tissue-Resident NK Cells during Decidualization in Mice. The Journal of Immunology, 201 (9) 2551-2556; DOI: 10.4049/jimmunol.1800651. Epub 2018 Oct 1.

Natural killer (NK) cells accumulate in a women’s uterus leading up to and during pregnancy. Uterine NK (uNK) cells come about from circulating progenitors (1). A progenitor cell is like a stem cell but it is more specific and is selected to differentiate into its target cell. The uteri of someone who is not pregnant also has an abundance of tissue-resident NK (trNK) cells but few conventional NK (cNK) cells. This study tracks the accumulation of uNK cells during pregnancy and identifies that both cNK and trNK cells accumulate in the myometrium, the smooth muscle tissue of the uterus, and decidua basalis, the part of the uterine lining that becomes the maternal part of the placenta. They show however, that only trNK cells have evidence of proliferation and suggest that proliferating trNK cells are the source of uNK cell accumulation on the lining of the uterus in preparation for and during pregnancy.

            NK cells are part of the innate (meaning inherent) immune system. They provide rapid responses and protection to viral infections and tumor formation. Different types of NK cells can be distinguished from one another. cNK cells are widely distributed NK cells that can migrate via the circulatory system (the system that transports blood and lymph through the body), whereas trNK cells remain in host tissue. These two types of NK cells also have phenotypic differences, meaning differences in observable characteristics, and depend on different transcription factors. Transcription factors are proteins that control the rate of transcription. There is current contradictions in the literature over whether accumulation of uNK cells during pregnancy preparation is due in part to a contribution of peripheral NK cells, or is there just expansion of current uNK cells that are resident to the uterus; or is it both (2). This study used a novel NK cell reporter mouse to visualize the rise of uNK cells during pregnancy. In other words, the study used a uNK cell-specific regulatory sequence to express a particular gene product that they could monitor, in order to determine where the cells are coming from. This was done primarily by using green florescent protein which exhibits bright green florescence when exposed to light in the blue to ultraviolet range. Their work found that uterine trNK cells proliferate locally, and are selectively proliferating early, in preparation for and during pregnancy and that cNK cells contributed only slightly to the overall accumulation.

Why is this Important?

This study provided clarity to the debate as to the origin of uNK cells during pregnancy. Accumulating NK cells consisted of proliferating trNK cells with cNK cells playing a negligible role. There were 10 times more trNK cells than cNK cells. The study also established that CD49a, a specific NK cell lineage (3), is a reliable marker of trNK cells in uterine tissue. There were cNK present that had migrated, but they were not proliferating once in the uterus. This data is important as it suggests possible new hypotheses as there may be multiple waves of NK cells accumulating at the uterus during pregnancy. The first wave being when the uterine lining starts to change in preparation of pregnancy. And then a second wave in which cNK cells are recruited from the periphery during placentation, the formation of the placenta in a women’s uterus, and changing of the spiral arteries, small arteries that temporarily provide blood to the lining of the uterus. Overall, the study suggests that pregnancy organizes the movement and maintenance of NK cell subgroups at different times, implying that each subgroup has distinct functions during pregnancy.

New Questions/Next Steps

            The logical next step would be to determine if the level of uNK cells stay constant throughout the pregnancy and if assistance from cNK cells is needed to do so. It may be determined that there is a decline in NK cell levels as the pregnancy develops. Another question could be, does this accumulation in uNK cells, described in the study, also take place when fertilization does not occur? 

References

1 - Basile, D. P., & Yoder, M. C. (2014). Circulating and tissue resident endothelial progenitor cells. Journal of cellular physiology, 229(1), 10-6.

2 - Chiossone, L., Vacca, P., Orecchia, P., Croxatto, D., Damonte, P., Astigiano, S., Barbieri, O., Bottino, C., Moretta, L., … Mingari, M. C. (2014). In vivo generation of decidual natural killer cells from resident hematopoietic progenitors. Haematologica, 99(3), 448-57.

3 - Marquardt, N., Béziat, V., Nyström, S., Hengst, J., Ivarsson, M.A., Kekäläinen, E., Johansson, H., Mjösberg, J., Westgren, M.M., Lankisch, T.O., Wedemeyer, H., Ellis, E.C., Ljunggren, H.G., Michaëlsson, J., & Björkström, N.K. (2015). Cutting edge: identification and characterization of human intrahepatic CD49a+ NK cells. Journal of immunology, 194 6, 2467-71. Current as of Oct. 25, 2018