Abstract
TGF-beta1 plays a critical role in restraining pathogenic Th1 autoimmune responses in vivo, but the mechanisms that mediate TGF-beta1's suppressive effects on CD4(+) T cell expression of IFN-gamma expression remain incompletely understood. To evaluate mechanisms by which TGF-beta1 inhibits IFN-gamma expression in CD4(+) T cells, we primed naive wild-type murine BALB/c CD4(+) T cells in vitro under Th1 development conditions in the presence or the absence of added TGF-beta1. We found that the presence of TGF-beta1 during priming of CD4(+) T cells suppressed both IFN-gamma expression during priming as well as the development of Th1 effector cells expressing IFN-gamma at a recall stimulation. TGF-beta1 inhibited the development of IFN-gamma-expressing cells in a dose-dependent fashion and in the absence of APC, indicating that TGF-beta1 can inhibit Th1 development by acting directly on the CD4(+) T cell. During priming, TGF-beta1 strongly inhibited the expression of both T-bet (T box expressed in T cells) and Stat4. We evaluated the importance of these two molecules in the suppression of IFN-gamma expression at the two phases of Th1 responses. Enforced expression of T-bet by retrovirus prevented TGF-beta1's inhibition of Th1 development, but did not prevent TGF-beta1's inhibition of IFN-gamma expression at priming. Conversely, enforced expression of Stat4 partly prevented TGF-beta1's inhibition of IFN-gamma expression during priming, but did not prevent TGF-beta1's inhibition of Th1 development. These data show that TGF-beta1 uses distinct mechanisms to inhibit IFN-gamma expression in CD4(+) T cells at priming and at recall.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism*
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Cell Division / genetics
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Cell Division / immunology
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Cells, Cultured
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Epitopes, T-Lymphocyte / immunology
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Female
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Gene Expression Regulation / immunology
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Growth Inhibitors / antagonists & inhibitors
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Growth Inhibitors / physiology
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Humans
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Immunization, Secondary*
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Interferon-gamma / antagonists & inhibitors*
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Interferon-gamma / biosynthesis*
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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STAT4 Transcription Factor
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Sensitivity and Specificity
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T-Box Domain Proteins
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T-bet Transcription Factor
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Th1 Cells / cytology
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Th1 Cells / immunology
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Th1 Cells / metabolism
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Trans-Activators / antagonists & inhibitors
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Trans-Activators / biosynthesis
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Trans-Activators / genetics
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Trans-Activators / physiology*
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / biosynthesis
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Transcription Factors / physiology*
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Transforming Growth Factor beta / deficiency
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / physiology*
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Transforming Growth Factor beta1
Substances
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DNA-Binding Proteins
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Epitopes, T-Lymphocyte
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Growth Inhibitors
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STAT4 Transcription Factor
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STAT4 protein, human
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Stat4 protein, mouse
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T-Box Domain Proteins
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T-bet Transcription Factor
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TGFB1 protein, human
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Tgfb1 protein, mouse
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Trans-Activators
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Transcription Factors
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Transforming Growth Factor beta
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Transforming Growth Factor beta1
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Interferon-gamma