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Regulatory effect of rat bone marrow mesenchymal stem cells on Treg/Th17 immune balance in vitro.

ABSTRACT: Bone marrow mesenchymal stem cells (BM?MSCs) regulate the balance between regulatory T cells (Tregs) and T helper 17 (Th17) cells. However, the role of different factors on BM?MSCs?mediated regulation of the Treg/Th17 balance is unknown. BM?MSCs and CD4+ T lymphocytes were co?cultured with various treatments. The ratio of Treg/Th17 cells was calculated and the expression of different cytokines was measured. BM?MSCs were found to have a proliferative effect on Th17 cells at a basal concentration and at a 2?fold increase in the number of BM?MSCs. However, when the number of BM?MSCs used was increased 4?fold, they had an inhibitory effect on the Th17 cells. The effect of BM?MSCs on Tregs was inhibited by the addition of tacrolimus but not rapamycin. The effect of BM?MSCs on Th17 cells was inhibited by rapamycin. Additionally, the effect of BM?MSCs on Tregs were inhibited by the addition of a transforming growth factor?? (TGF??) blocker, whereas these TGF???blockers had no effect on Th17 cells. Addition of an interleukin (IL)?2 blocker reduced the proportion of Th17 cells when co?cultured with a high number of MSCs compared with the low concentration group and the proportion of Treg cells was significantly decreased when cells were treated with an IL?2 blocker compared with the control group. Together, these results showed the varying effects of MSCs on the ratio of Treg/Th17, its dependence on the number of MSCs and the effects of cytokines in inducing these changes in the balance.

SUBMITTER: Wang K

PROVIDER: S-EPMC7115201 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Regulatory effect of rat bone marrow mesenchymal stem cells on Treg/Th17 immune balance in vitro.

Wang Kai K Shi Yan-Jun YJ Song Zhuo-Lun ZL Wu Bin B Zhou Chun-Lei CL Liu Wei W Gao Wei W

Molecular medicine reports 20200311 5

Bone marrow mesenchymal stem cells (BM‑MSCs) regulate the balance between regulatory T cells (Tregs) and T helper 17 (Th17) cells. However, the role of different factors on BM‑MSCs‑mediated regulation of the Treg/Th17 balance is unknown. BM‑MSCs and CD4+ T lymphocytes were co‑cultured with various treatments. The ratio of Treg/Th17 cells was calculated and the expression of different cytokines was measured. BM‑MSCs were found to have a proliferative effect on Th17 cells at a basal concentration ...[more]

PMID: 32186771

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Project description:INTRODUCTION:Mesenchymal stem cells (MSCs) exert immunomodulatory functions by inducing the development and differentiation of naive T cells into T cells with an anti-inflammatory regulatory T cell (Treg) phenotype. Our previous study showed that hepatocyte growth factor (HGF) secreted by MSCs had immunomodulatory effects in the context of lipopolysaccharide (LPS) stimulation. We hypothesized that HGF is a key factor in the MSC-mediated regulation of the T helper 17 (Th17) cell/regulatory T (Treg) cell balance. METHODS:We investigated the effects of MSCs on the differentiation of CD4+ T cells and the functions of Th17/Treg cells in response to LPS stimulation by performing in vitro coculture experiments. MSCs were added to the upper chambers of cell culture inserts, and CD4+ T cells were plated in the lower chambers, followed by treatment with LPS or an anti-HGF antibody. Th17 (CD4+CD3+RORrt+) and Treg (CD4+CD25+Foxp3+) cell frequencies were analysed by flow cytometry, and the expression of Th17 cell- and Treg cell-related cytokines in the CD4+ T cells or culture medium was measured by quantitative PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Neutrophil functions were determined by flow cytometry after a coculture with Th17/Treg cells. RESULTS:The percentage of CD4+CD25+Foxp3+ cells was significantly increased in the CD4+ T cell population, while the percentage of CD4+CD3+RORrt+ cells was significantly decreased after MSC coculture. However, the MSC-induced effect was significantly inhibited by the anti-HGF antibody (p?<?0.05). Furthermore, MSCs significantly inhibited the CD4+ T cell expression of IL-17 and IL-6 but increased the expression of IL-10 (p?<?0.05 or p?<?0.01); these effects were inhibited by the anti-HGF antibody (p?<?0.05). In addition, CD4+ T cells cocultured with MSCs significantly inhibited neutrophil phagocytic and oxidative burst activities (p?<?0.05 or p?<?0.01); however, these MSC-induced effects were inhibited by the anti-HGF antibody (p?<?0.05). CONCLUSION:These data suggested that MSCs induced the conversion of fully differentiated Th17 cells into functional Treg cells and thereby modulated the Th17/Treg cell balance in the CD4+ T cell population, which was partly attributed to HGF secreted by the MSCs.

Project description:Background and objectiveUmbilical cord (UC)-derived mesenchymal stem cells (MSCs) have shown immunoregulation of various immune cells. The aim of this study was to investigate the mechanism of UC MSCs in the regulation of peripheral regulatory T cells (Treg) and T helper 17 (Th17) cells in patients with systemic lupus erythematosus (SLE).MethodsThirty patients with active SLE, refractory to conventional therapies, were given UC MSCs infusions. The percentages of peripheral blood CD4+CD25+Foxp3+ regulatory T cells (Treg) and CD3+CD8-IL17A+ Th17 cells and the mean fluorescence intensities (MFI) of Foxp3 and IL-17 were measured at 1 week, 1 month, 3 months, 6 months, and 12 months after MSCs transplantation (MSCT). Serum cytokines, including transforming growth factor beta (TGF-β), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and IL-17A were detected using ELISA. Peripheral blood mononuclear cells from patients were collected and co-cultured with UC MSCs at ratios of 1:1, 10:1, and 50:1, respectively, for 72 h to detect the proportions of Treg and Th17 cells and the MFIs of Foxp3 and IL-17 were determined by flow cytometry. The cytokines in the supernatant solution were detected using ELISA. Inhibitors targeting TGF-β, IL-6, indoleamine 2,3-dioxygenase (IDO), and prostaglandin E2 were added to the co-culture system, and the percentages of Treg and Th17 cells were observed.ResultsThe percentage of peripheral Treg and Foxp3 MFI increased 1 week, 1 month, and 3 months after UC MSCs transplantation, while the Th17 proportion and MFI of IL-17 decreased 3 months, 6 months, and 12 months after the treatment, along with an increase in serum TGF-β at 1 week, 3 months, and 12 months and a decrease in serum TNF-α beginning at 1 week. There were no alterations in serums IL-6 and IL-17A before or after MSCT. In vitro studies showed that the UC MSCs dose-dependently up-regulated peripheral Treg proportion in SLE patients, which was not depended on cell-cell contact. However, the down-regulation of Th17 cells was not dose-dependently and also not depended on cell-cell contact. Supernatant TGF-β and IL-6 levels significantly increased, TNF-α significantly decreased, but IL-17A had no change after the co-culture. The addition of anti-TGF-β antibody significantly abrogated the up-regulation of Treg, and the addition of PGE2 inhibitor significantly abrogated the down-regulation of Th17 cells. Both anti-IL-6 antibody and IDO inhibitor had no effects on Treg and Th17 cells.ConclusionsUC MSCs up-regulate Treg and down-regulate Th17 cells through the regulation of TGF-β and PGE2 in lupus patients.

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Regulatory effect of rat bone marrow mesenchymal stem cells on Treg/Th17 immune balance in vitro.

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Regulatory effect of rat bone marrow mesenchymal stem cells on Treg/Th17 immune balance in vitro.

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