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TIM-3: a crucial regulator of NK cells in pregnancy

Cellular & Molecular Immunology volume 14, pages 948–950 (2017)Cite this article

In pregnancy, the maternal immune system (including innate and adaptive immunity) makes elaborate adjustments to endure the embryo’s expression of paternal antigens and to protect the embryo from attacks by invading pathogens such as bacteria or viruses.1 As the predominant innate immune cells during gestation, natural killer (NK) cells have been proven to mediate the establishment of maternal-fetal immune tolerance and to initiate appropriate defenses against infections.2 Tim-3, a member of the T-cell immunoglobulin and mucin domain proteins, has emerged as a key molecule in both innate and adaptive responses and represents a promising novel therapeutic target.3, 4 The expression of Tim-3 has been shown to associate with the maturation or activation of NK cells, and the surrounding immune microenvironment of NK cells also exerts some influence on Tim-3 expression. Accordingly, Tim-3 mediates the differential regulation of NK cell functions in specific physiologic or pathologic processes, playing a beneficial or detrimental role in immune status. It remains largely unknown how Tim-3 that is expressed on NK cells controls their functions during pregnancy.

The recent published data in this issue of Cellular and Molecular Immunology demonstrate the existence of a particular NK cell subset-Tim-3-expressing NK cell at the maternal-fetal interface.5 We characterized Tim-3+NK cell phenotypes and revealed how Tim-3 affects the activity of these innate immune cells in the context of pregnancy. Compared with Tim-3− decidual NK (dNK) cells, Tim-3+ dNK cells produced more T helper 2 (Th2)-typical cytokine, interleukin-4 (IL-4), but less Th1-typical cytokine, tumor necrosis factor-α (TNF-α). Perforin expression, an indicator of the cytotoxic activity of NK cells, was also significantly reduced in Tim-3+ dNK cells. Importantly, we showed a remarkably decreased percentage of Tim-3+ dNK cells in patients suffering miscarriages. In addition, a disturbed cytokine profile and increased cytotoxicity were observed in Tim-3+ dNK cells, but not in Tim-3− dNK cells from patients suffering miscarriages. These findings indicate that Tim-3 functions as a regulatory receptor on NK cells by reducing their cytotoxicity and modulating cytokine production in the context of gestation, which is similar to that in cancer and chronic infections. Tim-3 expressed on NK cells attenuates cell-mediated antitumor effects, serving a facilitating role in cancer.6, 7 Thus, Tim-3 blockade to reverse NK cell-mediated function could develop Tim-3-targeted tumor immune therapy.8 Similarly, the expression of Tim-3 on NK cells in gestation is conducive to the establishment and maintenance of maternal-fetal immune tolerance. Moreover, our unpublished data show that expanded Tim-3+ NK cells in maternal peripheral blood display immune-suppressive activity, including high-level production of anti-inflammatory cytokines and the induction of regulatory T (Treg) cell differentiation. Consistent with the downregulated expression of Tim-3 on dNK cells in miscarriages, Tim-3 expression on peripheral NK (pNK) cells was also compromised and was accompanied by impaired immune-suppressive activity. More importantly, Tim-3 blockade notably increased embryo resorption and led to dysfunctional NK cells in both the periphery and decidua. Combined with the above data, decreased expression of Tim-3 on NK cells may serve as a promising biological marker during pregnancy to predict the occurrence of miscarriage.

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Authors and Affiliations

  1. Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, China

    Yanhong Li, Dajin Li & Meirong Du

  2. Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Fudan University, Shanghai, China

    Yanhong Li, Dajin Li & Meirong Du

  3. Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China

    Yanhong Li, Dajin Li & Meirong Du

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Li, Y., Li, D. & Du, M. TIM-3: a crucial regulator of NK cells in pregnancy. Cell Mol Immunol 14, 948–950 (2017). https://doi.org/10.1038/cmi.2017.85

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