Altered vitamin D metabolism is involved in the dysregulation of γδT cell function and their crosstalk with trophoblasts in recurrent pregnancy loss

Abstract

Abstract Background Recurrent pregnancy loss (RPL) is a common disease characterized by immune dysfunction and vitamin D deficiency. This study aimed to investigate vitamin D metabolism and γδT cell phenotypes at the maternal–fetal interface in women with early normal pregnancy (NP) and RPL and to determine the effects of vitamin D on the functions of γδT cells and their crosstalk with trophoblasts. Methods The levels of 25‐(OH)VD 3 , the expression of vitamin D metabolic enzymes in the villi, and the proportion of γδT cells in the decidua were detected in women with NP and RPL. After treatment with different concentrations of vitamin D, the mRNA expression of the vitamin D receptor ( VDR ), cytokines, and transcription factors were detected in Vδ2 + γδT cells. In addition, the proliferation, migration, and invasion of HTR‐8/SVneo trophoblasts were determined by coculturing them with vitamin D‐treated Vδ2 + γδT cells and their supernatants. Results In women with RPL, the level of 25‐(OH)VD 3 in the villi was increased; however, that of CYP27B1 (enzyme converting 25‐(OH)VD 3 into 1,25‐(OH) 2 VD 3 ) was decreased. In addition, the proportion of Vδ2 + γδT cells increased, whereas that of Foxp3 + Vδ2 + γδT cells decreased in the decidua of women with RPL. An in vitro study showed that vitamin D increased the expression of VDR mRNA and Foxp3, but decreased the expression of IFN‐γ mRNA, in Vδ2 + γδT cells. Finally, vitamin D‐treated Vδ2 + γδT cells promoted trophoblast migration and invasion. Conclusions Abnormal vitamin D metabolism and γδT cell proportions were present at the maternal‐fetal interface in women with RPL. Under normal pregnancy conditions, vitamin D can induce the differentiation of decidual Vδ2 + γδT cells toward an anti‐inflammatory phenotype (Treg‐like γδT cells) and modulate the crosstalk between Vδ2 + γδT cells and trophoblasts.