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Transforming growth factor \(\beta\) (TGF-\(\beta\)) has a growth-inhibitory effect on numerous different cell types of the immune system, including T lymphocytes. We show in this study that the inhibitory action of TGF-\(\beta\) on T lymphocytes is accompanied by a block of interleukin 2 (IL-2) gene expression which is mediated, at least in part, by inhibition of IL-2 promoter/enhancer activity. The functional analysis of cis-regulatory (protoenhancer) elements of the IL-2 enhancer/promoter region showed that the most TGF-\(\beta\)-responsive element maps to its so-called upstream promoter site. The proto-enhancer activity of the upstream promoter site element is also inhibited by cyclosporin A. The upstream promoter site DNA harbors two noncanonical, closely linked binding sequences for octamer and AP-1-like factors. Both sites are involved in the establishment of IL-2 enhancer activity. Since the activity of genuine octamer sites but not that of AP-1-binding sites is also impaired by TGF-\(\beta\) and cyclosporin A in E14 T lymphoma cells, we conclude that both immunosuppressives interfere with the activity but not the DNA binding of octamer factors in T lymphocytes.
Cytotoxic T lymphocytes are effector CD8\(^{+}\) T cells that eradicate infected and malignant cells. Here we show that the transcription factor NFATc1 controls the cytotoxicity of mouse cytotoxic T lymphocytes. Activation of Nfatc1\(^{-/-}\) cytotoxic T lymphocytes showed a defective cytoskeleton organization and recruitment of cytosolic organelles to immunological synapses. These cells have reduced cytotoxicity against tumor cells, and mice with NFATc1-deficient T cells are defective in controlling Listeria infection. Transcriptome analysis shows diminished RNA levels of numerous genes in Nfatc1\(^{-/-}\) CD8\(^{+}\) T cells, including Tbx21, Gzmb and genes encoding cytokines and chemokines, and genes controlling glycolysis. Nfatc1\(^{-/-}\), but not Nfatc2\(^{-/-}\) CD8\(^{+}\) T cells have an impaired metabolic switch to glycolysis, which can be restored by IL-2. Genome-wide ChIP-seq shows that NFATc1 binds many genes that control cytotoxic T lymphocyte activity. Together these data indicate that NFATc1 is an important regulator of cytotoxic T lymphocyte effector functions.
Transcription factor AP-1 modulates the activity of the human foamy virus long terminal repeat
(1991)
The human foamy virus (HFV) contains within the UJ region of its long terminal repeat (L TR) three perfect consensus sequences for the binding of the inducible transcription factor AP-1. Results of DNase I footprint protection and gel retardation assays demonstrated that proteins in extracts of HeLa and BHK-21 cells as weil as bacterially expressed Jun and Fos proteins bind to these AP-1 sites. By conducting transient expression assays using chloramphenicol acetyltransferase plasmids carrying LTR sequences with point-mutated AP-1 sites it was found that the three AP-1 sites contribute to the optimal activity ofthe HFV promoter. It is shown that lnduction of the HFV L TR by 12-O-tetradecanoylphorbol-13-acetate (TPA) and serum factors is mediated through the AP-1 sites.