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Cytokine secretion by NK cells is abnormal in some women with recurrent pregnancy loss (RPL). Cytokine production is usually evaluated after stimulation with PMA and ionomycin. However, stimulation of uterine NK cells with semen corresponds more closely to physiological conditions at the time of conception. As seminal plasma has immunomodulatory properties, we aimed to elucidate compatibility between uterine NK cells and semen. Endometrial samples were stimulated with PMA/ionomycin, semen, seminal plasma, or spermatozoa. Thereafter, cytokine production by NK (CD56

Cytokine secretion by NK cells is abnormal in some women with recurrent pregnancy loss (RPL). Cytokine production is usually evaluated after stimulation with PMA and ionomycin. However, stimulation of uterine NK cells with semen corresponds more closely to physiological conditions at the time of conception. As seminal plasma has immunomodulatory properties, we aimed to elucidate compatibility between uterine NK cells and semen. Endometrial samples were stimulated with PMA/ionomycin, semen, seminal plasma, or spermatozoa. Thereafter, cytokine production by NK (CD56bright) cells was evaluated using flow cytometry and compared between women with and without a history of RPL associated with abnormal NK cell distribution in the endometrium or unexplained RPL. The ratios (%) of NK cells producing IFN-γ and TNF-α (NK1 phenotype), IL-4 (NK1/NK2 phenotype), and IL-10 (NK1/NKr1 phenotype) were significantly lower after stimulation with semen than with PMA/ionomycin (P < 0.01). After exposure to semen, ratios (%) of NK cells producing IL-4 and IL-10 in patients with unexplained RPL were significantly lower (P < 0.05), whereas those of NK1/NK2 and NK1/NKr1 were significantly higher (P < 0.01) than those in controls. The shift of endometrial NK cells to the NK2 phenotype was more pronounced when stimulated by semen than by PMA/ionomycin. However, a semen-induced shift to NK1 in women with unexplained RPL could induce miscarriage. Couple-specific immunological compatibility tests through semen stimulation in vitro might provide important information to avoid RPL.

The regulation of uterine and circulating peripheral blood natural killer (NK) cells has been associated with reproductive conditions including recurrent pregnancy loss (RPL), implantation failure and preeclampsia. Natural cytotoxicity receptors (NCRs) are unique markers that regulate NK cell cytotoxicity and cytokine production. The role of NCRs in reproductive events has not yet been fully characterized. There is an NK1 (Type 1) shift in peripheral blood NK cells in non-pregnant women prone to RPL and implantation failure. The different profile of NCR expression in endometrial or aborted decidual NK cells suggests the presence of abnormal regulation of NK cells in women with reproductive failure. Women with a history of RPL and preeclampsia carry immunological abnormalities of NCRs on peripheral blood NK cells during pregnancy. Evaluation of NKp46 on peripheral blood NK cells may be applicable for the prediction of preeclampsia. The lower expression of NKp46(+) NK cells in women with preeclampsia may account for the higher production of NK1 cytokines - known as the NK1 shift - in pregnant women with preeclampsia. In this review, the expression of NCRs in peripheral blood NK cells and endometrial or decidual NK cells is discussed in relation to reproductive failure.

Problem: It is considered that NK22 cells might mediate mucosal immune defense in several organ. In response to pathogen, IL-23 stimulates NK22 cells to secrete IL-22. It is only reported that NK22 cells were present in the uterinemucosa. Toexamine theNK22 function,we investigated theproductionand relationof IL-22and theother cytokines using endometrium (EM) and peripheral blood (PB) NK cells of women with recurrent pregnancy loss (RPL). Materials and methods: Cytokines production (IFNgamma, TNF-alpha, IL-4, IL-10, IL-22, TGF-b1) by PB and EMNK cells and the expression of Nkp46were analyzed by triple color flow cytometry inwomenwith RPL (n=43) and controls (n=38). Moreover, we classified into four groups with high or low percentage of IL-22 production (RPL-H, RPL-L, Control-H and Control-L). Results: In EM, the percentage of NK22 cells in women with RPL was significantly higher than that of controls (p

Problem: It is considered that NK22 cells might mediate mucosal immune defense in several organ. In response to pathogen, IL-23 stimulates NK22 cells to secrete IL-22. It is only reported that NK22 cells were present in the uterinemucosa. Toexamine theNK22 function,we investigated theproductionand relationof IL-22and theother cytokines using endometrium (EM) and peripheral blood (PB) NK cells of women with recurrent pregnancy loss (RPL). Materials and methods: Cytokines production (IFNgamma, TNF-alpha, IL-4, IL-10, IL-22, TGF-b1) by PB and EMNK cells and the expression of Nkp46were analyzed by triple color flow cytometry inwomenwith RPL (n=43) and controls (n=38). Moreover, we classified into four groups with high or low percentage of IL-22 production (RPL-H, RPL-L, Control-H and Control-L). Results: In EM, the percentage of NK22 cells in women with RPL was significantly higher than that of controls (p

PROBLEM: In the uterine endometrium and the first trimester decidua, there are a number of immune cells derived from the bonemarrow that are capable of responding to alloimmune stimulations from the embryo. Themain population of endometrial NK cell is cytokine producing CD16-/CD56bright NK cells, whereas the most abundant population in peripheral blood NK cells is cytotoxic CD16+/CD56dim NK cells. We previously reported that the increase in cytotoxic NK cells in peripheral blood and the endometrium have a beneficial effect on the therapeutic results of in vitro fertilization andembryo transfer (IVF-ET). Wehave also reported that seminal plasmaplays an important role in the recruitment of CD56bright NK cells into the endometrium. The present study was aimed to investigate the influence of sexual intercourse onNK cell subsets in the mid-secretory endometrium using flow cytometry. METHODS: This study was designed as a prospective study. All study subjects had signed informed consents prior to entry to this study, in accordance with local IRB protocol. All subjects who were planning to have invitro fertilization and embryo transfer (IVF-ET) had sexual intercourse before the endometrial sampling without any contraceptive devices. The mid-secretary endometrium was obtained from 234 women, and then submitted for flow cytometric analysis. Endomerial NK cell subpopulation was analyzed for the expression of CD16 and CD56 using 3-color flow cytometry. Semen analysis was performed at the time of oocytes pick up and was classified according to the World Health Organization (WHO) 2010 guideline. Of 234 semen samples, 10 were diagnosed as pyospermia (pyospermia group), and 224 as not-pyospermia (non-pyospermia group). RESULTS: There were no differences between 2 groups in the total sperm concentration and the motile sperm concentration, or in the percentage of CD56+ NK cells. The percentage of CD16-/CD56+ cells, however, was lower in pyospermia group (25.9±21.7%) compared with that in non-pyospermia group (35.4±18.2%). The percentage of CD16-/CD56bright cells was significantly lower in pyospermia group (28.0±27.8%) compared with that in not-pyospermia group (42.9±22.1%, p< 0.01). CONCLUSIONS: Our study firstly demonstrated that pyospermia has a harmful influence on endometrial NK cell subsets. The immunologically advantageous condition for successful pregnancies after sexual intercourse may give support to the hypothesis that seminal fluid may act as a regulator of endometrial immune cells and an inducer of feto-maternal immune tolerance. Further research should be undertaken to reveal the biological actions of seminal munology 94 (2012) 5–130