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 6

Adoptive transfer of TregsBlimp-1 improves pregnancy outcome in LPS-induced abortion-prone mouse model.

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Adoptive transfer of TregsBlimp-1 improves pregnancy outcome in LPS-indu...
(A) AT model diagram: LPS (2.5 μg) was injected i.p. on GD 9.5. After 2 hours and 24 hours, 2 × 105 cells/100 μL were transferred via i.v. Tregs were isolated from the spleen of donor mice through MACS. Mice were divided into 5 groups as follows (n = 8): NP, LPS, LPS+TregCtrl, LPS+TregBlimp-1, and LPS+TregIL-27. GD, gestational day. (B) Representative images of blastocysts and μCT scan results in different adoptive transfer (AT) groups. (C) Dynamic changes in body weight from GD 0.5 to 13.5 in different AT groups. (D) Embryonic resorption rates in different AT groups. (E) Placenta weight in different AT groups. (F) HE staining showing the morphological changes in mouse placenta following AT therapy. The first column shows the view under ×50 original magnification (scale bar: 500 μm), and the second through fourth columns show the corresponding magnified view under ×200 original magnification (scale bar: 200 μm). (G) CD31 staining on placental vascular formation in different AT groups. All images are shown under ×400 original magnification (scale bar: 100 μm). Data are represented as the mean ± SEM via 1-way ANOVA test and Tukey’s multiple comparisons test between each 2 groups (D and E). ***P < 0.001, ****P < 0.0001.