Endometrial natural killer cells reveal a tissue-specific receptor repertoire

19 April 2018

Cytotoxic natural killer (NK) cells are specialized in discriminating potentially dangerous cells and healthy “self” cells. For this reason, NK cells have classically been associated with antiviral and antitumor activity, but recent work suggests that they are also essential for ensuring healthy pregnancy.

In a report to Human Reproduction, Dorien Feyaerts (photo), Irma Joosten, Renate van der Molen, theme Inflammatory diseases, and colleagues demonstrated that these cells have a unique tissue-specific signature in the pre-pregnancy endometrium. This unusual finding suggests that endometrial NK cells are finely tuned to accept the semi-allogeneic fetus. Armed with this new knowledge, we can evaluate the programming of NK cells during pregnancy complications and potentially gain insight into the pathogenesis. 
 
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Pregnancy is considered an immunological conundrum. Although the developing fetus is foreign to the mother, i.e. 50% of its characteristics come from the father, it will be tolerated by the maternal immune system during pregnancy. Each month, during the menstrual cycle, the uterus prepares itself for pregnancy by a large influx of leukocytes in the endometrium (i.e. the mucosal lining of the non-pregnant uterus). After fertilization and implantation of an embryo into the endometrium, the number of leukocytes increases even further. Without implantation, the endometrial lining and its leukocytes are shed during menstruation. Natural killer (NK) cells are abundantly present in the human endometrium and will make up 70% of the uterine leukocytes during the first trimester of pregnancy.  

NK cells are classically defined as innate immune cells that are specialized in recognizing and killing of altered self-cells, i.e. tumor transformed or virus-infected cells. In the uterus however, NK cells don’t exhibit this killing capacity but display an important regulating role for successful pregnancy. After implantation of the embryo, NK cells will come in close contact with fetal-derived extravillous trophoblast cells (EVT). These NK cells will promote EVT invasion and spiral artery remodeling, thereby ensuring a correct formation of the placenta and an adequate blood supply to the fetus.

NK cell activity is regulated by different NK cell receptors (NKR), e.g. KIR and CD94/NKG2. NKR expression on NK cells in the placenta is affected by maternal HLA-C genotype and biased towards KIR2D expression. However, little is known about the regulation and composition of NKR expression on endometrial NK (eNK) cells. As NK cell activity is particularly relevant at the time of implantation, analysis of NKR expression may yield insight in the role of NKR+ eNK cells for successful pregnancy.

In this study, eNK cells, obtained from menstrual blood, were immunophenotyped for NKR expression with 10-color flow cytometry, and compared to peripheral blood NK (pbNK) cells of the same female.
We showed that, within the same female, the NKR expression profile of eNK cells does not differ over consecutive menstrual cycles. The NKR repertoire of eNK cells was clearly different from pbNK cells, with eNK cells co-expressing more than 3 NKR simultaneously. In addition, outlier analysis revealed 8 and 15 NKR subpopulation expansions in eNK and pbNK cells, respectively. In contrast to the pbNK cell population, the expansions present in the eNK cell population were independent of prior cytomegalovirus (CMV) infection and HLA-C genotype. Moreover, the typical NKG2C imprint induced by prior CMV infection on pbNK cells was not observed on eNK cells from the same female, collectively suggesting a rapid local turnover of eNK cells and/or a distinct licensing process. Follow up studies will focus in more detail on the mechanisms of eNK cell function.
Taken together, our data reveals that NK cells in the pre-implantation endometrium appear to have a dedicated tissue-specific phenotype, different from pbNK cells. This may indicate that eNK cells are finely tuned in ensuring a healthy pregnancy. Studying the endometrial NKR repertoire of women with pregnancy related problems, such as recurrent miscarriages, could provide clues to understand the pathogenesis. Perturbations in the endometrial immune cell composition could lead to the discovery of pregnancy-success related biomarkers and possibly even treatment options.