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

Abstract

Problem: Recurrent pregnancy loss (RPL) is one of the big challenges of normal pregnancy. Immune dysregulation has been proposed for the key underline mechanisms of RPL. However, the essential roles of T cells, especially γδ T cells, have not been defined. Method of study:Decidua were obtained from normal pregnancy women or recurrent pregnancy loss patients and the surface molecules of γδ T cells in decidua were evaluated via flow cytometric analysis. The expression of PD-1 in clinical samples was analyzed by immunohistochemistry assay. The intracellular cytokines of decidual PD-1 + and PD-1γδ T cells were evaluated by flow cytometric analysis. The cytotoxicity of PD-1γδ T cells were confirmed via an in vitro co-culture experiment. The specific inhibitors for Erk, p38 and JNK against the MAPK pathway were added to the co-culture media to evaluate the functions of the Erk, p38 and JNK. Results:We demonstrated that PD-1 was significantly decreased on decidual tissue γδ T cells of patients with RPL, resulting in the enhanced cytotoxicity of γδ T cells against trophoblasts. We further elucidated an Erk-dependent TNF-α production mediates the γδ T cell cytotoxicity against the trophoblast cells. Finally, the reduced expression of PD-L1 in the villi tissues of patients with RPL might be the cause of the reduction of PD-1 on the tissue γδ T cells.Rong Guo, Silin Jiang, and Jianliang Zhang contribute equally to this work.

The Key Resolver of Immune Tolerance: The Role of the PD-1/PD-L1 Signaling Pathway in Physiological and Pathological Pregnancy

“…In addition, PD-1 expression on CD4+ Tregs in the peripheral blood of RPL patients was significantly lower than in healthy first-trimester women (61). In a recent study, decreased PD-1 expression in decidual tissue γδ T cells of RPL patients, resulting in the enhanced cytotoxicity of γδ T cells against trophoblasts, was demonstrated (62). Moreover, the study also speculated that the decrease in PD-L1 expression in the villus tissues of patients with RPL may cause a decrease in PD-1 in tissue γδ T cells (62).…”

“…In a recent study, decreased PD-1 expression in decidual tissue γδ T cells of RPL patients, resulting in the enhanced cytotoxicity of γδ T cells against trophoblasts, was demonstrated (62). Moreover, the study also speculated that the decrease in PD-L1 expression in the villus tissues of patients with RPL may cause a decrease in PD-1 in tissue γδ T cells (62). In another study, Zhang and colleagues showed that NO deriving from M1 macrophages is critical for YY1/PD-L1 expression, which is essential for the maintenance of pregnancy (63).…”

Gamma delta (γδ) T cells in the female reproductive tract: active participants or indifferent bystanders in reproductive success?

“…Peripheral blood Vδ2 + cells have been shown to express more CD107a in recurrent miscarriage versus healthy pregnant women [ 98 ]. Furthermore, reduced PD-1 expression by decidual Vδ2 + cells in women with recurrent miscarriage may increase their cytotoxicity [ 99 ], potentially exacerbated by decreased RANK signaling and fewer RANK + regulatory γδ T cells in the decidua [ 76 ].…”

Human chorionic gonadotrophin indirectly activates peripheral γδT cells to produce interleukin‐10 during early pregnancy

“…γδΤ cells also exhibit cytotoxic potency and contribute to the anti‐infection defense during pregnancy 9 . Consequently, dysfunctional γδT cells are increasingly recognized as significant contributors to the development of pregnancy‐related complications 10–12 . A promising avenue of research involves the identification of factors that regulate the immune functions of γδT cells in early pregnancy.…”