Zhuhai Precision Medical Center, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Jinan University, Zhuhai, 519000, Guangdong, China.
The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou, 510632, Guangdong, China.
Cell Mol Immunol. 2021 Aug;18(8):1934-1944. doi: 10.1038/s41423-020-0499-3. Epub 2020 Jul 15.
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 Ca 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 influx and membrane potential (V)-induced Ca 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.
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，据报道其参与免疫调节，可能影响癌症发展的风险。然而，CFTR 对 γδ T 细胞的分化和功能的影响知之甚少。在本研究中，我们观察到 CFTR 在 γδ T 细胞的细胞表面上功能性表达。CFTR 的基因缺失和药理学抑制均增加了外周 γδ T 细胞 IFN-γ 的释放，并增强了这些细胞在体外和体内对肿瘤细胞的细胞毒性活性。有趣的是，CFTR 调节 γδ T 细胞 IFN-γ 产生的分子机制要么依赖于 TCR，要么与 Ca 流入有关。CFTR 被募集到 TCR 免疫突触，并减弱了 Lck-P38 MAPK-c-Jun 信号通路。此外，发现 CFTR 调节 TCR 诱导的 Ca 流入和膜电位（V）诱导的 Ca 流入，从而调节 γδ T 细胞中的钙调神经磷酸酶-NFATc1 信号通路。因此，CFTR 作为 γδ T 细胞 IFN-γ 产生的负调节剂和这些细胞在抗肿瘤免疫中的功能。我们的研究表明，修饰 γδ T 细胞的 CFTR 活性可能是癌症的一种潜在免疫治疗策略。
