NKG2D as a Cell Surface Marker on γδ-T Cells for Predicting Pregnancy Outcomes in Patients With Unexplained Repeated Implantation Failure

Abstract

Maternal immune tolerance to semi-allogeneic fetus is essential for a successful implantation and pregnancy. Growing evidence indicated that low cytotoxic activity of γδ-T cells, which is mediated by activation and inhibitory receptors, is important for establishment of maternal immune tolerant microenvironment. However, the correlation between receptors on peripheral blood γδ-T cells, such as NKG2D, CD158a, and CD158b, and pregnancy outcome in patients with unexplained repeated implantation failure (uRIF) remains unclear. In this study, the association between the expression level of these receptors and pregnancy outcome in patients with uRIF was investigated. Thirty-eight women with uRIF were enrolled and divided into two groups: successful group and failed group, according to the pregnancy outcome on different gestational periods. The percentage of NKG2D+ γδ-T cells in lymphocytes was significantly higher in uRIF patients who had failed clinical pregnancy in subsequent cycle, compared with those who had successful clinical pregnancy. However, there were no differences about the frequencies of CD158a+ and CD158b+ γδ-T cells between the successful and failed groups. The receiver operating characteristic curve exhibited that the optimal cut-off value of NKG2D+ γδ-T cells was 3.24%, with 92.3% sensitivity and 66.7% specificity in predicting clinical pregnancy failure in uRIF patients. The patients with uRIF were further divided into two groups, group 1 (NKG2D+ γδ-T cells <3.24%) and group 2 (NKG2D+ γδ-T cells ≥3.24%), based on the cut-off value. The live birth rate of patients in the group 1 and group 2 were 61.5 and 28.0%, respectively. Kaplan-Meier survival curve further suggested that the frequency of NKG2D+ γδ-T cells in lymphocytes negatively correlated with live birth rate in patients with uRIF. In conclusion, our study demonstrated that the frequency of peripheral blood NKG2D+ γδ-T cells among lymphocytes is a potential predictor for pregnancy outcome in uRIF patients.

Identification of key genes and immune cell infiltration in recurrent implantation failure: A study based on integrated analysis of multiple microarray studies

“…Meanwhile, γδ T cells also have the function of secreting pro‐inflammatory cytokines and cytotoxic molecules, which may exercise their cytotoxic potential in pathological pregnancy 38 . It has been reported that the percentage of granzyme B + γδ T 41 and NKG2D + γδ T 42 cells was significantly higher in peripheral blood lymphocytes of unexplained RIF patients who had failed clinical pregnancy in a subsequent cycle, compared with those who had successful clinical pregnancy. However, the number and function of immune cells in peripheral blood and endometrium are not completely the same or even very different 43 .…”

COVID-19 vaccination influences subtypes of γδ-T cells during pregnancy

“…NK cell activating receptors, such as NKG2D, NKp30, and NKp46, are widely involved in regulating NK functions during pregnancy ( 19 ). Additionally, one recent study suggested that the frequency of NKG2D + Vδ2 + T cells was negatively correlated with a successful clinical pregnancy ( 8 ). Our data demonstrate that no significant difference was found on the percentages of NKG2D + cells in Vδ1 + T cells and Vδ2 + T cells, which suggest that COVID-19 vaccination did not induce the highly activated peripheral γδ T cells in the pregnant women.…”

“…Although γδ-T cells represent only a small fraction of T lymphocytes (1-10%) ( 5 ), they have a variety of immune functions, such as resistance to virus infection ( 6 ), inflammatory regulation, tissue homeostasis ( 6 ), helping B cells to produce antibodies ( 7 ), and even maintenance of successful pregnancy ( 6 ). Some studies reported that, during normal human pregnancy, γδ-T cells secrete some anti-inflammatory cytokines to reduce nature killer activity ( 8 , 9 ).Indeed, γδ-T cells regulate the release of inflammatory factors such as IFN-γ,TNF-α, granzyme A/B, and perforin by regulating the expression of surface-activated receptors such as NKG2D, NKp30, NKP46, and the inhibitory receptor PD-1 to regulate their cytotoxic functions ( 10 – 13 ). In addition, low cytotoxic activity of γδ-T cells is necessary during normal pregnancy ( 14 ).…”

PD‐1 mediates decidual γδ T cells cytotoxicity during recurrent pregnancy loss

“…In addition, another study found that RANKL promoted the polarization of γδT cells on the decidua to Foxp3 + γδΤ cells to maintain pregnancy 32 . There are several studies focusing on the role of peripheral blood γδ T in predicting the failure of pregnancy 33‐35 . In particular, the mechanisms by which decidual γδ T cells contribute to the pathogenesis of RPL are not well defined 31 …”

“…32 There are several studies focusing on the role of peripheral blood γδ T in predicting the failure of pregnancy. [33][34][35] In particular, the mechanisms by which decidual γδ T cells contribute to the pathogenesis of RPL are not well defined. 31 PD-1 regulates the effector function of T cells under normal physiological and pathological conditions, and maintains immune homeostasis by limiting protective immunity, [36][37][38] while PD-L1, the ligand of PD-1, is usually highly expressed on tumor cells and other hematopoietic cells 39,40 protecting target organs against autoimmune attack.…”