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- Title
Inhibition of Glycogen Synthase Kinase 3β Increases the Proportion and Suppressive Function of CD19<sup>+</sup>CD24<sup>hi</sup>CD27<sup>+</sup> Breg Cells.
- Authors
Li, Jinyang; Gao, Ji; Zhou, Haoming; Zhou, Jinren; Deng, Zhenghua; Lu, Yunjie; Rao, Jianhua; Ji, Guwei; Gu, Jian; Yang, Xinxiang; Xia, Yongxiang; Wang, Xuehao
- Abstract
CD19+CD24hiCD27+ memory Breg cells exhibit decreased abundance in patients with chronic graft-versus-host disease (cGVHD) after liver transplantation and produce less IL-10 than those from patients without cGVHD and healthy donors. Due to the lack of Breg cells and the difficulty in expanding them in vitro , in mouse models and early human clinical trials, the adoptive transfer of Breg cells to autoimmune diseases is greatly restricted. Glycogen synthase kinase 3β (GSK-3β) is a multifunctional serine/threonine (ser/thr) protein kinase that can participate in B cell growth, metabolic activity, and proliferation. Phosphoprotein array analysis showed that p-GSK-3β-s9 was highly expressed in mBreg cells. Furthermore, here, we demonstrated that GSK-3β expression in mBreg cells is lower than that observed in B cells by flow cytometry. We found that the treatment of B cells with the specific GSK-3β inhibitor SB216763 can significantly increase the proportion and immunosuppressive function of mBreg cells in vitro. Nuclear factor of activated T cells (NFAT) is one of a pivotal regulator of gene expression in adaptive immune system. Here, we observed that inhibition of GSK-3β by SB216763 results in enhanced expression of NFATc1 in B cells, which is essential in regulating the ability of B cells to secrete IL-10. By constructing a xGVHD mouse model, we observed that SB216763-treated mBreg cells effectively prevent xenogeneic GVHD. Here we propose a novel strategy using SB216763 to inhibit GSK-3β and then enhance the proportion and immunosuppressive function of mBreg cells by increasing the expression of NFATc1. This approach may be used as a therapy to ameliorate GVHD and inflammatory diseases.
- Subjects
GLYCOGEN synthase kinase; NUCLEAR factor of activated T-cells; SERINE/THREONINE kinases; LIVER transplantation; GRAFT versus host disease; REGULATORY B cells
- Publication
Frontiers in Immunology, 2020, Vol 11, pN.PAG
- ISSN
1664-3224
- Publication type
Article
- DOI
10.3389/fimmu.2020.603288