Human chorionic gonadotropin potentially affects pregnancy outcome in women with recurrent implantation failure by regulating the homing preference of regulatory T cells

Abstract

Problem: Human chorionic gonadotropin (hCG) and regulatory T cells (Tregs) have been suggested to play important roles during the initial stage of pregnancy. However, the clinical relevance and mechanism of the effects of hCG on Treg functions in women with recurrent implantation failure (RIF) remain to be elucidated.

Method of study: Thirty-four RIF and twenty-three control women were included in the study. Endometrial and peripheral Tregs were analyzed by immunohistochemistry and flow cytometry, respectively. Tregs were generated from naïve CD4⁺ T cells by stimulation with anti-CD3/CD28 in the presence or absence of hCG, and the subsets were analyzed by flow cytometry, Western blotting, and qPCR.

Results: The percentages of endometrial FOXP3⁺ Tregs and peripheral CCR4⁺ FOXP3⁺ Tregs were significantly lower in the women with RIF than in the healthy controls. In addition, the percentages of CCR4⁺ FOXP3⁺ Tregs and TGF-β-expressing FOXP3⁺ Tregs were increased following the stimulation of naïve CD4⁺ T cells with anti-CD3/CD28, and these increases were concomitant with AKT and ERK dephosphorylation.

Conclusions: The results of this study provide novel evidence supporting a role of hCG in regulating the differentiation of peripheral FOXP3⁺ Tregs. The alterations of circulating Tregs may positively affect the pregnancy outcomes of patients with a history of RIF.

Keywords: chemokine-chemokine receptor; endometrial receptivity; human chorionic gonadotropin; recurrent implantation failure; regulatory T cells.