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The Galectin-9/Tim-3 pathway is involved in the regulation of NK cell function at the maternal–fetal interface in early pregnancy

Cellular & Molecular Immunology volume 13, pages 73–81 (2016)Cite this article

Abstract

Decidual natural killer (dNK) cells actively participate in the establishment and maintenance of maternal–fetal immune tolerance and act as local guardians against infection. However, how dNK cells maintain the immune balance between tolerance and anti-infection immune responses during pregnancy remains unknown. Here, we demonstrated that the inhibitory molecule T-cell immunoglobulin domain and mucin domain-containing molecule-3 (Tim-3) are expressed on over 60% of dNK cells. Tim-3+ dNK cells display higher interleukin (IL)-4 and lower tumor necrosis factor (TNF)-α and perforin production. Human trophoblast cells can induce the transformation of peripheral NK cells into a dNK-like phenotype via the secretion of galectin-9 (Gal-9) and the interaction between Gal-9 and Tim-3. In addition, trophoblasts inhibit lipopolysaccharide (LPS)-induced pro-inflammatory cytokine and perforin production by dNK cells, which can be attenuated by Tim-3 neutralizing antibodies. Interestingly, a decreased percentage of Tim-3-expressing dNK cells were observed in human miscarriages and murine abortion-prone models. Moreover, T helper (Th)2-type cytokines were decreased and Th1-type cytokines were increased in Tim-3+ but not Tim-3− dNK cells from human and mouse miscarriages. Therefore, our results suggest that the Gal-9/Tim-3 signal is important for the regulation of dNK cell function, which is beneficial for the maintenance of a normal pregnancy.

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Acknowledgements

This work was supported by the National Basic Research Program of China (2015CB943300); the Key Project of Shanghai Basic Research from the Shanghai Municipal Science and Technology Commission (STCSM) (12JC1401600 to DJ Li); the Key Project of Shanghai Municipal Education Commission (MECSM) (14ZZ013 to MR Du); the Extension Project of the Shanghai Health System (2013SY034 to MR Du); the Personnel Training Plan of the Health Care System (2013-3-021 to WH Zhou) and the Nature Science Foundation of the National Nature Science Foundation of China (NSFC) (NSFC31270969 to DJ Li; NSFC81070537, NSFC31171437 and NSFC81370770 to MR Du; NSFC81270753 to WH Zhou; NSFC31300751 to HL Piao; NSFC81370730 to Q Fu).

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Author notes

  1. Yan-Hong Li and Wen-Hui Zhou: These authors contributed equally to this work.

  2. Dr MR Du, Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China. E-mail: dmrlq1973@sina.cn

Authors and Affiliations

  1. Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China

    Yan-Hong Li, Yu Tao, Song-Cun Wang, Di Zhang, Hai-Lan Piao, Qiang Fu, Da-Jin Li & Mei-Rong Du

  2. Medical Center for Human Reproduction, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China

    Wen-Hui Zhou

  3. Maternal and Child Care Hospital of Huangpu District, Shanghai, China

    Yun-Lan Jiang

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Li, YH., Zhou, WH., Tao, Y. et al. The Galectin-9/Tim-3 pathway is involved in the regulation of NK cell function at the maternal–fetal interface in early pregnancy. Cell Mol Immunol 13, 73–81 (2016). https://doi.org/10.1038/cmi.2014.126

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