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GLI2 regulates TGF-β1 in human CD4+ T cells: implications in cancer and HIV pathogenesis
Robert L Furler1, Christel H Uittenbogaart
1Department of Microbiology, Immunology, and Molecular Genetics, David E Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
Abstract:
Elevated levels of the immunoregulatory cytokine TGF-β1 in cancer and HIV infection have been linked to the suppression of protective immune responses. The transcriptional regulation of TGF-β1 is complex and still not completely understood. We report here for the first time that the transcription factor GLI2 regulates the expression of TGF-β1 in human CD4(+) T cells. In silico screening revealed five novel putative GLI binding sites in the human TGF-β1 promoter. At least two of these sites within the human TGF-β1 promoter are regulated by the GLI2 activator as knockdown of GLI2 in regulatory CD4(+)CD25(hi) T cells, high producers of TGF-β1, significantly decreased TGF-β1 transcription. Additionally, naïve CD4(+) T cells, low producers of TGF-β1, increased their basal level of TGF-β1 mRNA following lentiviral infection with GLI2. The transcriptional regulation of TGF-β1 by GLI2 is a new extension to Sonic Hedgehog (SHH) and TGF-β1 cross-regulation and may provide insight into the detrimental elevation of TGF-β1 leading to pathogenesis in cancer and HIV infection.
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