Accumulation of γδT cells in the decidua is promoted by RANKL which upregulates ICAM-1 via NF-κB

in Reproduction
Authors:
Rui-Qi Chang The Center for Reproductive Medicine, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
Joint International Research Lab for Reproduction and Development, Ministry of Education, Chongqing, People’s Republic of China
Reproduction and Stem Cell Therapy Research Center of Chongqing, Chongqing, People’s Republic of China

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Jing-Cong Dai The Center for Reproductive Medicine, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China

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Yu-Han Qiu The Center for Reproductive Medicine, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China

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Yan Liang The Center for Reproductive Medicine, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China

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Xiao-Yu Hu The Center for Reproductive Medicine, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China

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Ming-Qing Li Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, People’s Republic of China

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https://orcid.org/0000-0002-9276-0722
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Fan He The Center for Reproductive Medicine, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
Joint International Research Lab for Reproduction and Development, Ministry of Education, Chongqing, People’s Republic of China
Reproduction and Stem Cell Therapy Research Center of Chongqing, Chongqing, People’s Republic of China

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https://orcid.org/0000-0003-2000-7894

Correspondence should be addressed to F He or M Li; Email: dr.hefan@cqmu.edu.cn or mqli@fudan.edu.cn
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In brief

The mechanism underlying the accumulation of γδT cells in the decidua, which helps maintain maternal–fetal immunotolerance in early pregnancy, is unknown. This study reveals that DSC-derived RANKL upregulates ICAM-1 expression via the NF-κB pathway to enable γδT cell accumulation in the early decidua.

Abstract

Decidual γδT (dγδT) cells help maintain maternal–fetal immunotolerance in early pregnancy. However, the mechanism underlying the accumulation of γδT cells in the decidua is unknown. Previous work showed that RANKL upregulated intercellular adhesion molecule 1 (ICAM-1) in decidual stromal cells (DSCs), and Rankl knockout mice had limited dγδT cell populations. In this study, we measured the expression levels of RANKL/RANK and ICAM-1 in DSCs, in addition to the integrins of ICAM-1 on dγδT cells, and the number of dγδT cells from patients with recurrent spontaneous abortion (RSA) and normal pregnant women in the first trimester. RSA patients showed significantly decreased RANKL/RANK and ICAM-1/CD11a signaling in decidua, and a decreased percentage of dγδT cells, which was positively correlated with DSC-derived RANKL and ICAM-1. Next, an in vitro adhesion experiment showed that the enhanced attraction of human DSCs to dγδT cells after RANKL overexpression was almost completely aborted by anti-ICAM-1. Furthermore, Rankl knockout mice showed a significant reduction in NF-κB activity compared with wild-type controls. Finally, we applied a selective NF-κB inhibitor named PDTC to validate the role of NF-κB in RANKL-mediated ICAM-1 upregulation. Taken together, our data show that DSC-derived RANKL upregulates ICAM-1 expression via the NF-κB pathway to enable γδT cell accumulation in the early decidua. A reduction in RANKL/ICAM-1 signaling in DSCs may result in insufficient accumulation of γδT cells in decidua and, in turn, RSA.

 

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