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

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 gamma delta T cell phenotypes at the maternal-fetal interface in women with early normal pregnancy (NP) and RPL and to determine the effects of vitamin Don the functions of gamma delta T cells and their crosstalk with trophoblasts. Methods: The levels of 25-(OH)VD3, the expression of vitamin D metabolic enzymes in the villi, and the proportion of gamma delta T 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 V delta 2(+)gamma delta T cells. In addition, the proliferation, migration, and invasion of HTR-8/SVneo trophoblasts were determined by coculturing them with vitamin D-treated V delta 2(+)gamma delta T cells and their supernatants. Results: In women with RPL, the level of 25-(OH)VD3 in the villi was increased; however, that of CYP27B1 (enzyme converting 25-(OH)VD3 into 1,25-(OH)(2)VD3) was decreased. In addition, the proportion of V delta 2(+)gamma delta T cells increased, whereas that of Foxp3(+)V delta 2(+)gamma delta T 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-gamma mRNA, in V delta 2(+)gamma delta T cells. Finally, vitamin D-treated V delta 2(+)gamma delta T cells promoted trophoblast migration and invasion. Conclusions: Abnormal vitamin D metabolism and gamma delta T 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 V delta 2(+)gamma delta T cells toward an anti-inflammatory phenotype (Treg-like gamma delta T cells) and modulate the crosstalk between V delta 2(+)gamma delta T cells and trophoblasts.