A possible mechanism of impaired NK cytotoxicity in cancer patients: down-regulation of DAP10 by TGF-beta 1

Abstract

Aims and background. Elevated TGF-beta 1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. However, the molecular mechanism of immunosuppression by TGF-beta 1 is not yet clarified. Methods. IL-2-activated human NK cells were cultured with TGF-beta 1. Protein levels of NKG2D and DAP10 were examined by FAGS or immunoblot analyses. Real-time RTPCR was performed to quantify the transcription levels. MAPK inhibitors were used to investigate intracellular signaling. Results. TGF-beta 1 down-regulated total and surface NKG2D, which was partially dependent on transcriptional regulation. TGF-beta 1 treatment of human NK cells resulted in significant changes in both transcriptional and translational levels of DAP10. Moreover, treatment with bafilomycin A1 or folimycin restored total NKG2D levels in TGF-beta 1-treated NK cells. The impaired NKG2D down-modulation by TGF-beta 1 was not associated with activation of the MAPK signaling pathway. Conclusions. TGF-beta 1 down-modulates surface NKG2D expression by controlling the transcriptional and translational levels of DAP10.