Co-expression of NKp46 with activating or inhibitory receptors on, and cytokine production by, uterine endometrial NK cells in recurrent pregnancy loss

Takeyama, Ryu; Fukui, Atsushi; Mai, Chuxian; Yamamoto, Mayu; Saeki, Shinichiro; Yamaya, Ayano; Shibahara, Hiroaki

doi:10.1016/j.jri.2021.103324

Cited by 13 publications

(15 citation statements)

References 29 publications

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“…In addition, a recent study found an altered cytokine secretion profile of eNK cells in women with RM. Unlike in women with normal fertility, the TNF-α/IL-4, IFN-γ/IL4, TNF-α/IL-10, and IFN-γ/IL10 ratios in eNK cells were significantly elevated in women with RM ( 128 ). The results indicate the association of changes in the receptor and cytokine profiles of eNK cells with RM.…”

Section: Unk Cells Under Pathological Conditionsmentioning

confidence: 82%

“…Several studies have demonstrated that higher proportions of NKp46 + CD56 + eNK cell populations may result in a greater risk of infertility ( 126 ). However, recent reports suggest that low expression of the NKp46 receptor on eNK cells is more common in women at high-risk for RM ( 70 , 128 ). In one study, NKp46 + eNK cells were classified into low-expression (NKp46 dim eNK) and high-expression (NKp46 bright eNK) groups according to different fluorescence intensities.…”

Section: Unk Cells Under Pathological Conditionsmentioning

confidence: 99%

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Uterine Natural Killer Cells: A Rising Star in Human Pregnancy Regulation

Xie

Meng

et al. 2022

Front. Immunol.

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Uterine natural killer (uNK) cells are an immune subset located in the uterus. uNK cells have distinct tissue-specific characteristics compared to their counterparts in peripheral blood and lymphoid organs. Based on their location and the pregnancy status of the host, uNK cells are classified as endometrial NK (eNK) cells or decidua NK (dNK) cells. uNK cells are important in protecting the host from pathogen invasion and contribute to a series of physiological processes that affect successful pregnancy, including uterine spiral artery remodeling, fetal development, and immunity tolerance. Abnormal alterations in uNK cell numbers and/or impaired function may cause pregnancy complications, such as recurrent miscarriage, preeclampsia, or even infertility. In this review, we introduce recent advances in human uNK cell research under normal physiological or pathological conditions, and summarize their unique influences on the process of pregnancy complications or uterine diseases. Finally, we propose the potential clinical use of uNK cells as a novel cellular immunotherapeutic approach for reproductive disorders.

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Section: Unk Cells Under Pathological Conditionsmentioning

confidence: 82%

Section: Unk Cells Under Pathological Conditionsmentioning

confidence: 99%

Uterine Natural Killer Cells: A Rising Star in Human Pregnancy Regulation

Xie

Meng

et al. 2022

Front. Immunol.

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“…19 Recently, we reported that the numbers of NKp46 + CD16 − NK cells were low in patients with higher CD56 dim /CD16 + NK cells, accompanied by an NK2 shift. 20 We have also reported that NKp46 dim NK cells may be involved in NK cell cytotoxicities, whereas NKp46 bright NK cells may be involved in cytokine production, suggesting that NKp46 could be a predictive marker for immune tolerance in pregnancy. 21 There are two types of NK cells: NK1 cells producing inflammatory (Type 1) cytokines, such as IFNγ and TNFα, and NK2 cells producing anti-inflammatory (Type 2) cytokines, such as IL-4 and IL-10.…”

mentioning

confidence: 77%

“…[27][28][29] Besides, we have also reported that low expression of activating receptors on NKp46 + uNK cells is more prevalent in high-risk women. 20 Thus, NKp46 plays an important role in reproduction through cytotoxicity and cytokine production. However, the detailed mechanism remains unknown and NKp46 expression on dNK cells in patients with RPL has not been investigated.…”

mentioning

confidence: 99%

Evaluation of NKp46 expression and cytokine production of decidual NK cells in women with recurrent pregnancy loss

Yamamoto¹,

Fukui²,

Mai³

et al. 2022

Reprod Medicine & Biology

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Recurrent pregnancy loss (RPL) is defined as two or more clinical pregnancy losses. 1 Approximately 60% of patients with RPL have repeated, unexplained miscarriages without common diagnoses, such as uterine malformation, the presence of antiphospholipid antibodies, thyroid dysfunction, or abnormal karyotypes in couples. 2 Such unexplained miscarriages are possibly due to fetal chromosomal abnormalities or dysfunctional maternal immune responses.An embryo is a semi-allograft with paternal alloantigens recognized by the maternal immune system. 3,4 In early pregnancy, the inflammatory immune response is necessary for successful implantation. In particular, cytotoxic immune effectors at the maternal-fetal interface protect a fetus from pathogens while participating in tissue

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“…On the other hand, there are reports that RM is associated with increased uNK production of TNFα and IFN-γ, although a major limitation is that all of these studies were performed on decidua collected after miscarriage hence associated with the confounding factor of inflammatory processes occurring after a miscarriage. (Dong et al, 2017;Liu et al, 2019Liu et al, , 2020Fonseca et al, 2020;Takeyama et al, 2021). There is some evidence that TNFα inhibits EVT invasion by mechanisms such as trophoblast apoptosis, inhibition of proliferation and reduced matrix metalloprotease production (Lash et al, 2006;Otun et al, 2011).…”

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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Co-expression of NKp46 with activating or inhibitory receptors on, and cytokine production by, uterine endometrial NK cells in recurrent pregnancy loss

Cited by 13 publications

References 29 publications

Uterine Natural Killer Cells: A Rising Star in Human Pregnancy Regulation

Uterine Natural Killer Cells: A Rising Star in Human Pregnancy Regulation

Evaluation of NKp46 expression and cytokine production of decidual NK cells in women with recurrent pregnancy loss

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

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