Natural killer cell profiles in recurrent pregnancy loss: Increased expression and positive associations with TACTILE and LILRB1

Habets, Denise H J; Schlütter, Anna; Kuijk, Sander M J van; Spaanderman, Marc E. A.; Al‐Nasiry, Salwan; Wieten, Lotte

doi:10.1111/aji.13612

Cited by 9 publications

(4 citation statements)

References 53 publications

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“…It has been suggested that these cells could account for the greater likelihood of success in second and subsequent pregnancies (49) and if so, this would be consistent with a role for LILRB1 in optimizing placental development. For women with reproductive failure, studies on LILRB1 have mostly concentrated on pNK in RM patients (39,50) except for one study on uNK using termination samples stratified by uterine artery resistance (51). On balance, and in line with our findings, these studies reported reduced expression of LILRB1 in women with high risk of reproductive problems.…”

Section: Discussionsupporting

confidence: 81%

Uterine NK cells underexpress KIR2DL1/S1 and LILRB1 in reproductive failure

et al. 2023

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A significant proportion of recurrent miscarriage, recurrent implantation failure and infertility are unexplained, and these conditions have been proposed to have an etiology of immunological dysfunction at the maternal-fetal interface. Uterine Natural Killer cells (uNK) comprise three subsets and are the most numerous immune cells found in the uterine mucosa at the time of implantation. They are thought to play an important role in successful pregnancy by regulation of extravillous trophoblast (EVT) invasion and spiral artery remodelling. Here, we examine the frequency, phenotype and function of uNK1-3 from the uterine mucosa of 16 women with unexplained reproductive failure compared to 11 controls with no reproductive problems, during the window of implantation. We report that KIR2DL1/S1 and LILRB1 expression is lower in the reproductive failure group for both uNK (total uNK, uNK 2 and 3) and pNK. We also show that degranulation activity is significantly reduced in total uNK, and that TNF-α production is lower in all uNK subsets in the reproductive failure group. Taken together, our findings suggest that reproductive failure is associated with global reduction in expression of uNK receptors important for interaction with HLA-C and HLA-G on EVT during early pregnancy, leading to reduced uNK activation. This is the first study to examine uNK subsets during the window of implantation in women with reproductive failure and will serve as a platform to focus on particular aspects of phenotype and function of uNK subsets in future studies. Further understanding of uNK dysregulation is important to establish potential diagnostic and therapeutic targets in the population of women with unexplained reproductive failure.

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Section: Discussionsupporting

confidence: 81%

Uterine NK cells underexpress KIR2DL1/S1 and LILRB1 in reproductive failure

et al. 2023

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“…Notably, a recent study by Habets et al found increased expression of CD96 on PBMCs from recurrent pregnancy loss samples, in contrast to the current study that found reduced CD96 expression on dNK cells. Many phenotypic differences between peripheral blood immune cells and maternal–foetal interface immune cells have been reported, and the underlying mechanisms of the differential phenotypic changes in CD96 at the peripheral blood and maternal–foetal interfaces need further exploration [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Palmitic Acid Upregulates CD96 Expression to Mediate Maternal–Foetal Interface Immune Tolerance by Inhibiting Cytotoxic Activity and Promoting Adhesion Function in Human Decidual Natural Killer Cells

Wang,

Wang

2023

Bioengineering

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Decidual natural killer cells (dNK cells) are an essential component of the immune cells present at the maternal–foetal interface during early pregnancy, and they play a vital role in various physiological processes. Abnormalities in the ratio or function of dNK cells have been linked to recurrent miscarriages. CD96 has been previously shown to regulate NK cell function in the tumour microenvironment; however, its role and mechanism at the maternal–foetal interface remains unclear. The present study aimed to investigate the immunomodulatory role of CD96 in dNK cells and its function at the maternal–foetal interface. Immunofluorescence staining and flow cytometry were used to detect the expression of cellular markers such as CD96. Furthermore, the secretory function, adhesion-function-related molecules, and cell proliferation markers of CD96+ and CD96− dNK cells were detected using flow cytometry. In addition, we performed cell culture experiments via the magnetic bead sorting of NK cells to detect changes in the expression of the aforementioned functional molecules in dNK cells after the CD96 blockade. Furthermore, we examined the functional characteristics of dNK cells after palmitic acid treatment at a concentration of 10 μM. We also examined the changes in dNK cell function when subjected to the combined effect of palmitic acid and CD96 antagonists. The results indicated that CD96, TIGIT, CD155, and CD112 were highly expressed at the maternal–foetal interface, with dNK cells predominantly expressing CD96, whereas TIGIT was mainly expressed on T cells, and CD155 and CD112 were mainly present in metaphase stromal and trophoblast cells. CD96+ dNK cells displayed low cytotoxic activity and a high adhesion phenotype, which mediated the immunosuppressive effect on dNK cells at the maternal–foetal interface. Palmitic acid upregulated CD96 expression on the surface of dNK cells in the coculture system, inhibiting dNK cell activity and increasing their adhesion molecule expression. CD96 antagonist treatment blocked the inhibitory effect of trophoblasts on dNK cells, resulting in enhanced cytokine secretion and reduced adhesion. The results of this study provide valuable insight into the immunomodulatory role of CD96 in dNK cells and its mechanism at the maternal–foetal interface, particularly in metaphase NK cells. This study sheds light on the mechanisms of immune regulation at the maternal–foetal interface and their implications for the study of recurrent miscarriages of unknown origin.

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“…It has been suggested that these cells could account for the greater likelihood of success in second and subsequent pregnancies (Goldman-Wohl et al ., 2019) and if so, this would be consistent with a role for LILRB1 in optimizing placental development. For women with reproductive failure, studies on LILRB1 have mostly concentrated on pNK in RM patients (Kniotek et al ., 2021; Habets et al ., 2022) except for one study on uNK using TOP samples stratified by uterine artery resistance (Wallace et al ., 2014). On balance, and in line with our findings, these studies reported reduced expression of LILRB1 in women with high risk of reproductive problems.…”

Section: Discussionmentioning

confidence: 99%

Uterine NK cells underexpress receptors recognizing HLA-C2 and HLA-G in reproductive failure

Woon

Nikolaou

Maclaran

et al. 2022

Preprint

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A significant proportion of recurrent miscarriage, recurrent implantation failure and infertility are unexplained, and these conditions have been proposed to have an etiology of immunological dysfunction at the maternal-fetal interface. Uterine Natural Killer cells (uNK) comprise three subsets and are the most numerous immune cells found in the uterine mucosa at the time of implantation. They are thought to play an important role in successful pregnancy by regulation of extravillous trophoblast (EVT) invasion and spiral artery remodelling. Here, we examine the frequency, phenotype and function of uNK1-3 from the uterine mucosa of 16 women with unexplained reproductive failure compared to 11 controls with no reproductive problems, during the window of implantation. We report that KIR2DL1/S1 and LILRB1 expression is lower in the reproductive failure group for both uNK (total uNK, uNK 2 and 3) and pNK. We also show that degranulation activity is significantly reduced in total uNK, and that TNF-α production is lower in all uNK subsets in the reproductive failure group. Taken together, our findings suggest that reproductive failure may be caused by global reduction in expression of uNK receptors important for interaction with HLA-C and HLA-G on EVT during early pregnancy, leading to reduced uNK activation. This is the first study to examine uNK subsets during the window of implantation in women with reproductive failure and will serve as a platform to focus on particular aspects of phenotype and function of uNK subsets in future studies. Further understanding of uNK dysregulation is important to establish potential diagnostic and therapeutic targets in the population of women with unexplained reproductive failure.

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Natural killer cell profiles in recurrent pregnancy loss: Increased expression and positive associations with TACTILE and LILRB1

Cited by 9 publications

References 53 publications

Uterine NK cells underexpress KIR2DL1/S1 and LILRB1 in reproductive failure

Uterine NK cells underexpress KIR2DL1/S1 and LILRB1 in reproductive failure

Palmitic Acid Upregulates CD96 Expression to Mediate Maternal–Foetal Interface Immune Tolerance by Inhibiting Cytotoxic Activity and Promoting Adhesion Function in Human Decidual Natural Killer Cells

Uterine NK cells underexpress receptors recognizing HLA-C2 and HLA-G in reproductive failure

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