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Decidual RANKL/RANK interaction promotes the residence and polarization of TGF-?1-producing regulatory ?? T cells.

ABSTRACT: ABSTACT:Decidual ??? (d???) cells play an essential role during successful pregnancy; however, the residence and polarization of ??? cells in decidua remain unclear. In this study, we observed higher levels of receptor activator for nuclear factor-? B ligand (RANKL) on decidual stromal cells (DSCs), and its receptor RANK on d??? cells in decidua from normal pregnancy compared with patients with recurrent spontaneous abortion (RSA). RANKL expressed by DSCs can induce the polarization of peripheral blood ??? (p???) and d??? cells to Foxp3?+???? cells, and upregulate the expression of transforming growth factor (TGF)-?1. This process is mediated through activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B). In addition, RANKL promotes the adhesion of d??? cells to DSCs in vitro, which is associated with the upregulation of ICAM-1 and VCAM-1 on DSCs and integrins on d??? cells. RANKL knockout leads to the decreased numbers of uterus total ??? cells, Foxp3+??? cells and the expression of TGF-?1, and the increased pregnancy loss in mice. These results suggest that RANKL is a pivotal regulator of maternal-fetal tolerance by triggering the polarization and residence of TGF-?1-producing Foxp3+??? cells in early pregnancy. The abnormal low level of RANKL/RANK results in pregnancy loss because of the dialogue disorder between DSCs and d??? cells. This observation provides a scientific basis on which a potential marker can be detected to early warning of pregnancy loss.

SUBMITTER: Chang RQ

PROVIDER: S-EPMC6368618 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Decidual RANKL/RANK interaction promotes the residence and polarization of TGF-β1-producing regulatory γδ T cells.

Chang Rui-Qi RQ Shao Jun J Meng Yu-Han YH Wang Jian J Li Da-Jin DJ Li Ming-Qing MQ

Cell death & disease 20190208 2

<h4>Abstact</h4>Decidual γδΤ (dγδΤ) cells play an essential role during successful pregnancy; however, the residence and polarization of γδΤ cells in decidua remain unclear. In this study, we observed higher levels of receptor activator for nuclear factor-κ B ligand (RANKL) on decidual stromal cells (DSCs), and its receptor RANK on dγδΤ cells in decidua from normal pregnancy compared with patients with recurrent spontaneous abortion (RSA). RANKL expressed by DSCs can induce the polarization of p ...[more]

PMID: 30737372

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Project description:Inflammatory mechanisms influence tumorigenesis and metastatic progression even in cancers whose aetiology does not involve pre-existing inflammation or infection, such as breast and prostate cancers. For instance, prostate cancer metastasis is associated with the infiltration of lymphocytes into advanced tumours and the upregulation of two tumour-necrosis-factor family members: receptor activator of nuclear factor-?B (RANK) ligand (RANKL) and lymphotoxin. But the source of RANKL and its role in metastasis have not been established. RANKL and its receptor RANK control the proliferation of mammary lobuloalveolar cells during pregnancy through inhibitor of nuclear factor-?B (I?B) kinase-? (IKK-?), a protein kinase that is needed for the self-renewal of mammary cancer progenitors and for prostate cancer metastasis. We therefore examined whether RANKL, RANK and IKK-? are also involved in mammary/breast cancer metastasis. Indeed, RANK signalling in mammary carcinoma cells that overexpress the proto-oncogene Erbb2 (also known as Neu), which is frequently amplified in metastatic human breast cancers, was important for pulmonary metastasis. Metastatic spread of Erbb2-transformed carcinoma cells also required CD4(+)CD25(+) T cells, whose major pro-metastatic function was RANKL production. Most RANKL-producing T cells expressed forkhead box P3 (FOXP3), a transcription factor produced by regulatory T cells, and were located next to smooth muscle actin (SMA)(+) stromal cells in mouse and human breast cancers. The dependence of pulmonary metastasis on T cells was replaceable by exogenous RANKL, which also stimulated pulmonary metastasis of RANK(+) human breast cancer cells. These results are consistent with the adverse impact of tumour-infiltrating CD4(+) or FOXP3(+) T cells on human breast cancer prognosis and suggest that the targeting of RANKL-RANK can be used in conjunction with the therapeutic elimination of primary breast tumours to prevent recurrent metastatic disease.

Dataset Information

Decidual RANKL/RANK interaction promotes the residence and polarization of TGF-?1-producing regulatory ?? T cells.

Publications

Decidual RANKL/RANK interaction promotes the residence and polarization of TGF-β1-producing regulatory γδ T cells.

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