Cftr Is A Negative Regulator Of Gamma Delta T Cell Ifn-Gamma Production And Antitumor Immunity

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.