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Published on: January 22, 2020
CFTR is a negative regulator of γδ T cell IFN-γ production and antitumor immunity
Yuanyuan Duan1,2, Guangqiang Li1,2, Miaomiao Xu1,2
1Zhuhai Precision Medical Center, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Jinan University, Zhuhai, 519000, Guangdong, China.
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.
Insights
Cystic fibrosis transmembrane conductance regulator (CFTR) negatively regulates gamma delta T cell functions. Inhibiting CFTR enhances anti-tumor immunity, suggesting CFTR as a potential cancer immunotherapy target.
Area of Science:
- Immunology
- Cell Biology
- Cancer Research
Background:
- Cystic fibrosis transmembrane conductance regulator (CFTR) is known for its role in epithelial cells and has been implicated in immune regulation and cancer risk.
- The specific effects of CFTR on gamma delta (γδ) T cells, crucial components of the immune system, remain largely unexplored.
Purpose of the Study:
- To investigate the expression and function of CFTR in γδ T cells.
- To elucidate the role of CFTR in regulating γδ T cell-mediated anti-tumor immunity.
Main Methods:
- Functional assessment of CFTR expression on γδ T cells.
- Genetic deletion and pharmacological inhibition of CFTR.
- Measurement of Interferon-gamma (IFN-γ) release and cytolytic activity.
- Analysis of signaling pathways including TCR, Lck-P38 MAPK-c-Jun, and calcineurin-NFATc1.
Main Results:
- CFTR is functionally expressed on the surface of γδ T cells.
- CFTR inhibition or deletion significantly increased IFN-γ production and enhanced γδ T cell cytotoxicity against tumor cells in vitro and in vivo.
- CFTR negatively regulates γδ T cell activation by modulating TCR signaling, calcium influx, and downstream pathways.
Conclusions:
- CFTR acts as a negative regulator of γδ T cell function and anti-tumor immunity.
- Targeting CFTR activity in γδ T cells presents a promising avenue for cancer immunotherapy development.
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