Foxp3 TSDR Hypermethylation Is Correlated with Decreased Tregs in Patients with Unexplained Recurrent Spontaneous...

A decline of T regulatory cell (Treg) number and function is associated with unexplained recurrent spontaneous abortion (URSA). However, the mechanism of downregulation of Tregs in URSA patients is still unknown. This study aimed to investigate the changes of Tregs in URSA patients and the epigenetic regulation for these changes. Venous blood samples were collected from 20 patients with URSA and 20 healthy control subjects. Treg number and inhibitory capacity, and Foxp3 mRNA expression and Foxp3 TSDR methylation were compared between the 2 groups. Correlations between Treg frequency and inhibitory function and TSDR methylation status were examined by Spearman's correlation. The proportion of Tregs within the population of CD4⁺ T cells and the expression of Foxp3 mRNA was significantly lower in URSA patients than in healthy control subjects. Tregs from URSA patients and healthy controls both significantly inhibited the cytotoxic activity of natural killer (NK) cells toward K562 targets; however, the inhibitory ability of Tregs from URSA patients was significantly lower than that from healthy controls. The methylation level of the Treg-specific demethylated region (TSDR) in the Foxp3 gene was significantly greater in URSA patients than in the controls, and the level of methylation was inversely correlated with the proportion of Tregs and Foxp3 mRNA expression in the peripheral blood. However, the methylation level was not correlated with the inhibitory function of Tregs. A decrease of Treg number and function may be related to the pathogenesis of URSA, and Foxp3 hypermethylation may be associated with the decreased Treg number.