CFTR is a negative regulator of γδ T cell IFN-γ production and antitumor immunity
CFTR is a negative regulator of γδ T cell IFN-γ production and antitumor immunity
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CFTR 是 γ δ T 细胞 IFN-γ 产生和抗肿瘤免疫的负调节因子
DOI：
10.1038/s41423-020-0499-3
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发表时间：
2020-07-15
影响因子：
24.1
通讯作者：
Yin, Zhinan
中科院分区：
文献类型：
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作者：
Duan, Yuanyuan;Li, Guangqiang;Yin, Zhinan
CFTR 是一种氯离子通道和离子通道调节剂，主要在上皮细胞中研究，据报道它参与免疫调节，并可能影响癌症发展的风险。然而，人们对CFTR对γδT细胞分化和功能的影响知之甚少。在这项研究中，我们观察到 CFTR 在 γ δ T 细胞的细胞表面功能性表达。 CFTR 的基因缺失和药理学抑制既增加了外周 γ δ T 细胞的 IFN-γ 释放，又增强了这些细胞在体外和体内针对肿瘤细胞的细胞溶解活性。有趣的是，CFTR调节γδT细胞IFN-γ产生的分子机制要么依赖于TCR，要么与Ca(2+)流入相关。 CFTR 被招募到 TCR 免疫突触并减弱 Lck-P38 MAPK-c-Jun 信号传导。此外，CFTR被发现可以调节TCR诱导的Ca(2+)内流和膜电位(V-m)诱导的Ca(2+)内流，并随后调节γδT细胞中的钙调神经磷酸酶-NFATc1信号通路。因此，CFTR 作为 γ δ T 细胞中 IFN-γ 产生以及这些细胞在抗肿瘤免疫中的功能的负调节因子。我们的研究表明，改变 γδT 细胞的 CFTR 活性可能是一种潜在的癌症免疫治疗策略。
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 gamma delta T cells. In this study, we observed that CFTR was functionally expressed on the cell surface of gamma delta T cells. Genetic deletion and pharmacological inhibition of CFTR both increased IFN-gamma release by peripheral gamma delta 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 gamma delta T cell IFN-gamma production by CFTR were either TCR dependent or related to Ca(2+)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 Ca(2+)influx and membrane potential (V-m)-induced Ca(2+)influx and subsequently regulate the calcineurin-NFATc1 signaling pathway in gamma delta T cells. Thus, CFTR serves as a negative regulator of IFN-gamma production in gamma delta T cells and the function of these cells in antitumor immunity. Our investigation suggests that modification of the CFTR activity of gamma delta T cells may be a potential immunotherapeutic strategy for cancer.