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Inflammation negatively regulates FOXP3 and regulatory T-cell function via DBC1
- Gao, Yayi, Tang, Jiayou, Chen, Weiqian, Li, Qiang, Nie, Jia, Lin, Fang, Wu, Qingsi, Chen, Zuojia, Gao, Zhimei, Fan, Huimin, Tsun, Andy, Shen, Jijia, Chen, Guihua, Liu, Zhongmin, Lou, Zhenkun, Olsen, Nancy J., Zheng, Song Guo, Li, Bin
- Proceedings of the National Academy of Sciences of the United States of America 2015 v.112 no.25 pp. E3246
- T-lymphocytes, breast neoplasms, homeostasis, humans, immune response, inflammation, interleukin-6, tumor necrosis factor-alpha
- Significance Treg cells suppress excessive and aberrant immune responses. Impaired function or homeostasis of Treg cells would induce severe autoimmune and inflammatory diseases. Forkhead box P3 (FOXP3), as a master regulator of Treg cells, forms a large complex with other binding factors to modulate Treg-cell function subtly in pathological and physiological conditions. We identified that Deleted in breast cancer 1 (DBC1) is an essential subunit of the FOXP3 complex in human CD4 ⁺ Treg cells. Our results show that the inflammatory cytokines TNF-α or IL-6 trigger FOXP3 degradation, whereas downregulation of DBC1 expression prevents FOXP3 degradation and maintains Treg-cell function under inflammatory stimuli in vitro and in vivo. These findings unveil a previously unidentified pathway for therapeutically modulating FOXP3 ⁺ Treg-cell stability under inflammation.