PD-1 mediates decidual gamma delta T cells cytotoxicity during recurrent pregnancy loss

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 gamma delta 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 gamma delta 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-1- gamma delta T cells were evaluated by flow cytometric analysis. The cytotoxicity of PD-1- gamma delta 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 gamma delta T cells of patients with RPL, resulting in the enhanced cytotoxicity of gamma delta T cells against trophoblasts. We further elucidated an Erk-dependent TNF-alpha production mediates the gamma delta 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 gamma delta T cells. Conclusion: Our study uncovers an important role of PD-1 expression on decidual gamma delta T cells in maintaining the normal pregnancy, and may provide a new strategy for immune therapy against RPL.