IL-27/Blimp-1 axis regulates the differentiation and function of Tim-3+ Tregs during early pregnancy
Si-Jia Zhao, Xiao-Hui Hu, Xin-Xiu Lin, Yu-Jing Zhang, Jing Wang, Huan Wang, Guang-Shun Gong, Gil Mor, Ai-Hua Liao
Si-Jia Zhao, Xiao-Hui Hu, Xin-Xiu Lin, Yu-Jing Zhang, Jing Wang, Huan Wang, Guang-Shun Gong, Gil Mor, Ai-Hua Liao
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Research Article Immunology Reproductive biology

IL-27/Blimp-1 axis regulates the differentiation and function of Tim-3+ Tregs during early pregnancy

Abstract

Decidual regulatory T cells (Tregs) are essential for successful pregnancy outcome. A subset of Tregs, T cell immunoglobulin and mucin domain-containing protein 3–positive regulatory T cells (TregsTim-3+), plays a central role in the acceptance of the fetus during early stages of normal pregnancy. The molecular mechanism regulating the differentiation and function of TregsTim-3+ is unknown. Here, we investigated the role of the transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1) on decidual TregTim-3+ differentiation. We demonstrated that Blimp-1 enhanced the coexpression of negative costimulatory molecules (Tim-3, T cell immunoreceptor with Ig and ITIM domains, and programmed cell death protein 1) on Tregs and improved their immunosuppressive functions, including increased IL-10 secretion, suppression of effector T cell proliferation, and promotion of macrophage polarization toward the M2 phenotype. Furthermore, we showed that IL-27 regulated the expression of Tim-3 and Blimp-1 through the STAT1 signaling pathway and that transfer of TregsBlimp-1+ into an abortion-prone mouse model effectively reduced embryo absorption rate. We postulated that abnormalities in the IL-27/Blimp-1 axis might be associated with recurrent pregnancy loss (RPL). These findings provided insights for developing more efficient immunotherapies for women with RPL.

Authors

Si-Jia Zhao, Xiao-Hui Hu, Xin-Xiu Lin, Yu-Jing Zhang, Jing Wang, Huan Wang, Guang-Shun Gong, Gil Mor, Ai-Hua Liao

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Figure 1

Comparison of the dynamic expression of Tim3 on decidual Tregs and peripheral Tregs during pregnancy.

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Comparison of the dynamic expression of Tim3 on decidual Tregs and perip...
(A) Experimental workflow and collection of PBMCs and decidual tissue samples (undergoing digestion in 37°C water bath swing) from early, middle, and late pregnancy for flow cytometry (FCM). (B) Gating strategy for peripheral and decidual Tim-3+CD4+ T cells and Tim-3+ Tregs. (C) Dynamic changes in the proportion of Tim-3+CD4+ T cells and Tim-3+ Tregs in decidua during the first, second, and third trimesters. (D) Comparison of the proportion of Tim-3+CD4+ T cells and Tim-3+ Tregs in peripheral and decidua during the first trimester. (E) Principal component analysis (PCA) plot generated of BT, IT, and PT groups by using the R-ggplot2 package. (F) Volcano plots showing differentially expressed genes between BT and PT, as well as between BT and IT groups. (G) Heatmap displaying all genes, immune-related molecules, and transcription factors in the BT, IT, and PT groups. BT, peripheral Treg; IT, Treg in decidua basalis; PT, Treg in decidua parietalis. Data are represented as the mean ± SEM via 1-way ANOVA test (C) and unpaired, 2-tailed Student’s t test (D). **P < 0.01, ***P < 0.001.