Abstract
Transforming growth factor-beta1 (TGF-beta1) is a pluripotent cytokine that controls peripheral T cell tolerance mainly in mucosal immunity. It is secreted by regulatory T cells (Tr /Th3) but also by other immununologically active cells. Smad anchor for receptor activation (SARA) and hepatic growth factor-regulated tyrosine kinase substrate (Hgs) are involved in TGF-beta1 signaling. Both molecules are known to present Smad2 and Smad3 to the TGF-beta receptor complex. The role of SARA and Hgs in TGF-beta1 susceptibility of human CD4+ T cells is unclear. We demonstrate here that TGF-beta1 up-regulates SARA mRNA expression in CD4+ T cells similar to that of Smad7. However, the increase in SARA expression was lower (6.1+/-0.3-fold vs. 25+/-4.1-fold) compared with Smad7 and delayed, with a maximum at 12 h compared with 2 h. Th1 and Th2 cell subsets expressed the same levels of SARA and Hgs. Compared with resting cells, significantly lower levels of the two molecules were found in antigen/allergen- or anti-CD3/CD28-stimulated cells. Down-regulation of SARA and Hgs mRNA in preactivated CD4+ T cells was accompanied by a twofold increase in a TGF-beta1 responsive reporter gene assay. Overexpression of SARA and Hgs in T cells yielded a dose-dependent decrease in cotransfected reporter gene expression, indicating an inhibitory function of both molecules. Thus, SARA and Hgs are regulators of TGF-beta1 susceptibility in T cells and integrate regulatory signals into the influence of TGF-beta1-mediated suppression of human T cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Allergens / pharmacology
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Antibodies / pharmacology
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CD28 Antigens / immunology
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CD3 Complex / immunology
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / metabolism
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Carrier Proteins / genetics
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Carrier Proteins / physiology*
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Cell Line
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Endosomal Sorting Complexes Required for Transport
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Gene Expression Regulation / drug effects
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Green Fluorescent Proteins
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Humans
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Interferon-gamma / pharmacology
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Interleukin-2 / pharmacology
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Intracellular Signaling Peptides and Proteins*
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Jurkat Cells
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Luminescent Proteins / genetics
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Luminescent Proteins / metabolism
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Lymphocyte Activation / drug effects
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Phosphoproteins / genetics
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Phosphoproteins / physiology*
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RNA, Messenger / drug effects
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Serine Endopeptidases*
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T-Lymphocytes / drug effects*
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T-Lymphocytes / metabolism
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Th1 Cells / drug effects
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Th1 Cells / metabolism
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Th2 Cells / drug effects
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Th2 Cells / metabolism
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Transfection
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Transforming Growth Factor beta / pharmacology*
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Transforming Growth Factor beta1
Substances
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Allergens
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Antibodies
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CD28 Antigens
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CD3 Complex
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Carrier Proteins
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Endosomal Sorting Complexes Required for Transport
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Interleukin-2
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Intracellular Signaling Peptides and Proteins
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Luminescent Proteins
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Phosphoproteins
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RNA, Messenger
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Recombinant Fusion Proteins
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TGFB1 protein, human
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Transforming Growth Factor beta
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Transforming Growth Factor beta1
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hepatocyte growth factor-regulated tyrosine kinase substrate
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Green Fluorescent Proteins
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Interferon-gamma
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ZFYVE16 protein, human
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Serine Endopeptidases