*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
