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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.