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CD4+Foxp3+ regulatory T cell differentiation mediated by endometrial stromal cell-derived TECK promotes the growth and invasion of endometriotic lesions.

ABSTRACT: Endometriosis is associated with an abnormal immune response to endometrial cells, which can facilitate the implantation and proliferation of ectopic endometrial tissue. The proportion of CD4(+)Foxp3(+) regulatory T cells (Tregs) is significantly increased in the peritoneal fluid of women with endometriosis. The thymus-expressed chemokine TECK/CCL25 directly promotes the invasiveness of endometrial stromal cells (ESCs). The aim of this study was to investigate the effects of ESC-derived TECK on the crosstalk between Tregs and ESCs in the progress of endometriosis. We determined that the percentage of Tregs and the concentration of TECK increased in the peritoneal fluid with the progression of endometriosis. The supernatant from co-cultured human ESCs and macrophages not only induced Treg differentiation and increased Treg expression of interleukin-10 (IL-10), transforming growth factor-? (TGF-?) and CD73 by activating the AKT/STAT3 signaling pathway but also repressed Treg apoptosis by downregulating Fas and FasL expression and enhanced the Treg-mediated suppression of CD4(+)CD25(-) T cells. In addition, in vitro and in vivo trials confirmed that these effects could be inhibited by anti-TECK neutralizing Abs. The secretion of IL-10 and TGF-? by Tregs increased MMP2 expression and decreased TIMP1 expression and further stimulated the proliferation and invasion of ESCs and the growth of ectopic lesions. These results indicate that TECK derived from ESCs and macrophages upregulates the number and function of Tregs in the ectopic milieu, which contributes to endometriotic immunotolerance and high levels of ESC proliferation and invasion, thereby facilitating the progression of endometriosis.

SUBMITTER: Li MQ

PROVIDER: S-EPMC4649519 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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CD4+Foxp3+ regulatory T cell differentiation mediated by endometrial stromal cell-derived TECK promotes the growth and invasion of endometriotic lesions.

Li M-Q MQ Wang Y Y Chang K-K KK Meng Y-H YH Liu L-B LB Mei J J Wang Y Y Wang X-Q XQ Jin L-P LP Li D-J DJ

Cell death & disease 20141002

Endometriosis is associated with an abnormal immune response to endometrial cells, which can facilitate the implantation and proliferation of ectopic endometrial tissue. The proportion of CD4(+)Foxp3(+) regulatory T cells (Tregs) is significantly increased in the peritoneal fluid of women with endometriosis. The thymus-expressed chemokine TECK/CCL25 directly promotes the invasiveness of endometrial stromal cells (ESCs). The aim of this study was to investigate the effects of ESC-derived TECK on ...[more]

PMID: 25275597

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Project description:Endometriosis is an inflammatory disease that presents with ectopic endometriotic lesions. Reduced immunosurveillance of these lesions has been proposed to be playing a role in the pathology of endometriosis. Mesenchymal stromal cells (MSC) are found in ectopic lesions and may decrease immunosurveillance. In the present study, we examined if MSC contribute to reduced immunosurveillance through their immunosuppressive effects on natural killer (NK) cells. Stromal cells from endometriotic ovarian cysts (ESCcyst) and eutopic endometrium (ESCendo) of women with endometriosis and their conditioned medium were used in co-cultures with allogeneic peripheral blood NK cells. Following culture, NK cells were examined phenotypically for their expression of activating, inhibitory, maturation, and adhesion receptors and co-receptors, as well as the degranulation (CD107a) marker and the immunostimulatory (interferon-γ) and immunosuppressive (transforming growth factor beta 1 and interleukin-10) cytokines. Moreover, NK cell cytotoxicity was examined using chromium 51 release killing assays. There were no differences between ESCcyst and ESCendo regarding their effects on NK cell cytotoxicity in both conditioned medium and direct co-culture experiments. Additionally, there were no differences between ESCcyst and ESCendo regarding their impact on NK cells' phenotype and degranulation in both conditioned medium and direct co-culture experiments. Although there were no differences found for DNAX accessory molecule-1 (DNAM-1) and NKp44, we found that the expression of the NK cell ligand CD155 that binds DNAM-1 and proliferating cell nuclear antigen (PCNA) that binds NKp44 was significantly less on ESCcyst than on ESCendo. These findings were not supported by the results that the expression of the known and unknown ligands on ESCcyst for DNAM-1 and NKp44 using chimeric proteins was not significantly different compared to ESCendo. In conclusion, the results suggest that ectopic MSC may not contribute to reduced immunosurveillance in endometriosis through their inhibitory effects on NK cells. This suggests that NK cell inhibition in the pelvic cavity of women with endometriosis develops due to other factors.

Dataset Information

CD4+Foxp3+ regulatory T cell differentiation mediated by endometrial stromal cell-derived TECK promotes the growth and invasion of endometriotic lesions.

Publications

CD4+Foxp3+ regulatory T cell differentiation mediated by endometrial stromal cell-derived TECK promotes the growth and invasion of endometriotic lesions.

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