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 2

Dynamic expression of Blimp-1 in the first, second, and third trimesters during pregnancy and its correlation with Tim-3.

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Dynamic expression of Blimp-1 in the first, second, and third trimesters...
(A) Immunohistochemistry (IHC) staining of Blimp-1 expression in different groups; the upper row shows the view under ×100 original magnification, and the lower row shows the corresponding magnified view (×400 original magnification). Scale bar: 100 μm. (B) Colocalization of Blimp-1 with CK7 and vimentin in decidua. CK7, a marker of trophoblast cells; vimentin, a marker of decidual stromal cells. The first through third columns are at ×200 original magnification (scale bar: 100 μm), while the fourth column shows the corresponding view under ×400 original magnification (scale bar: 50 μm). (C) Colocalization of Blimp-1, CD4, and Foxp3 in decidua Blimp-1+ cells and CD4+Foxp3+Blimp-1+ cells, and all images are shown under ×400 original magnification (scale bar: 50 μm). (D) Comparison of the proportion of Blimp-1+ Tregs and Blimp-1+CD4+ T cells in PBMCs and decidua of normal early pregnancy by FCM. (E) Pearson’s correlation analysis between the proportion of Blimp-1+ Tregs and Tim-3+ Tregs and between the proportion of Blimp-1+CD4+ T cells and Tim-3+CD4+ T cells in decidua. Data are presented as the mean ± SEM, by unpaired, 2-tailed Student’s t test (D). *P < 0.05, ****P < 0.0001.