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CFTR is a negative regulator of γδ T cell IFN-γ production and antitumor immunity
Authors:Yuanyuan Duan  Guangqiang Li  Miaomiao Xu  Xiaofei Qi  Mingxia Deng  Xuejia Lin  Zhiwei Lei  Yi Hu  Zhenghu Jia  Quanli Yang  Guangchao Cao  Zonghua Liu  Qiong Wen  Zhenhua Li  Jie Tang  Wei Kevin Zhang  Pingbo Huang  Limin Zheng  Richard A. Flavell  Jianlei Hao  Zhinan Yin
Abstract:CFTR, a chloride channel and ion channel regulator studied mostly in epithelial cells, has been reported to participate in immune regulation and likely affect the risk of cancer development. However, little is known about the effects of CFTR on the differentiation and function of γδ T cells. In this study, we observed that CFTR was functionally expressed on the cell surface of γδ T cells. Genetic deletion and pharmacological inhibition of CFTR both increased IFN-γ release by peripheral γδ T cells and potentiated the cytolytic activity of these cells against tumor cells both in vitro and in vivo. Interestingly, the molecular mechanisms underlying the regulation of γδ T cell IFN-γ production by CFTR were either TCR dependent or related to Ca2+ influx. CFTR was recruited to TCR immunological synapses and attenuated Lck-P38 MAPK-c-Jun signaling. In addition, CFTR was found to modulate TCR-induced Ca2+ influx and membrane potential (Vm)-induced Ca2+ influx and subsequently regulate the calcineurin-NFATc1 signaling pathway in γδ T cells. Thus, CFTR serves as a negative regulator of IFN-γ production in γδ T cells and the function of these cells in antitumor immunity. Our investigation suggests that modification of the CFTR activity of γδ T cells may be a potential immunotherapeutic strategy for cancer.
Keywords:CFTR, γ  δ   T cells, TCR, Membrane potential, Antitumor immunity
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