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Decidualization-derived cAMP regulates phenotypic and functional conversion of decidual NK cells from CD56dimCD16− NK cells

Cellular & Molecular Immunology volume 18, pages 1596–1598 (2021)Cite this article

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In early pregnancy, the decidua is populated by a large number of natural killer cells (NKs), most of which are CD56bright with a strong capacity to secrete cytokines, differing from peripheral and cord blood NK cells (pNKs and cNKs).1,2,3 It is generally believed that uterine NKs are recruited from the peripheral blood and are further educated to develop a decidual NK cell (dNK)-like phenotype in the microenvironment at the maternal-fetal interface.4 However, the defined mechanisms involved in this education remain unclear.

During decidualization, cAMP is a critical substance for efficient decidualization, which can also be produced by decidualized ESCs, resulting in a large amount of cAMP accumulating at the maternal-fetal interface.7,8 We then postulated that cAMP produced during decidualization prompts phenotypic transformation of dNKs. As expected, cAMP treatment significantly upregulated CD56 expression on cNKs and pNKs (Fig. 1b, Supplementary Fig. 3). Additionally, the cytokine-producing ability of cNKs, including the production of IL-10 and IFN-α, was upregulated with cAMP treatment, while cytotoxicity was downregulated, with lowered expression of Granzyme B and NKP44 and decreased release of LDH, when cNKs were cocultured with the human first-trimester extravillous trophoblast cell line HTR8. In addition, CFSE staining indicated the role of cAMP in promoting cNK proliferation (Fig. 1b). Of note, the increased proportion of CD56brightCD16− NKs was still maintained at a high level when pretreatment with mitomycin C was used to inhibit cell proliferation before administration of cAMP (Supplementary Fig. 4), suggesting that cAMP induced the phenotypic conversion of NK cells from CD56dimCD16− to CD56brightCD16−. Moreover, metadoxine (META), an inhibitor of the protein kinase A-cAMP pathway that inhibits CREB phosphorylation and binds to the cAMP response element,9 decreased the expression of CD56 on dNKs, accompanied by increased expression of Perforin and Granzyme B and decreased production of IFN-γ and IL-4 in the dNKs (Fig. 1c). Both cAMP treatment and META treatment identified the importance of cAMP signaling in NK phenotypic maintenance and transformation.

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Acknowledgements

This work was supported by the National Basic Research Program of China (2017YFC1001403), the National Nature Science Foundation of China (31970859, 81630036, and 91542116), the Innovation-oriented Science and Technology Grant from the NHC Key Laboratory of Reproduction Regulation (CX2017-2), The Strategic Collaborative Research Program of the Ferring Institute of Reproductive Medicine Supported by Ferring Pharmaceuticals and the Chinese Academy of Sciences (FIRMX200504), the funding for the Innovative Research Team of High-level Local Universities in Shanghai and a key laboratory program of the Education Commission of Shanghai Municipality (ZDSYS14005).

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  1. These authors contributed equally: Xueling Jin, Liyuan Cui.

Authors and Affiliations

  1. NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, China

    Xueling Jin, Liyuan Cui, Weijie Zhao, Xinyi Li, Lu Liu, Yanhong Li, Qiang Fu, Dajin Li, Min Yu & Meirong Du

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

    Xueling Jin, Liyuan Cui, Weijie Zhao, Xinyi Li, Lu Liu, Yanhong Li, Qiang Fu, Dajin Li, Min Yu & Meirong Du

  3. Department of Immunology, Binzhou Medical College, Yantai, China

    Qiang Fu

  4. Department of Obstetrics and Gynecology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China

    Meirong Du

  5. State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, SAR, China

    Meirong Du

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  1. Xueling Jin
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Correspondence to Meirong Du.

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Jin, X., Cui, L., Zhao, W. et al. Decidualization-derived cAMP regulates phenotypic and functional conversion of decidual NK cells from CD56dimCD16− NK cells. Cell Mol Immunol 18, 1596–1598 (2021). https://doi.org/10.1038/s41423-021-00675-y

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