SARA and Hgs attenuate susceptibility to TGF-beta1-mediated T cell suppression

FASEB J. 2003 Feb;17(2):194-202. doi: 10.1096/fj.02-0550com.


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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allergens / pharmacology
  • Antibodies / pharmacology
  • CD28 Antigens / immunology
  • CD3 Complex / immunology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / metabolism
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology*
  • Cell Line
  • Endosomal Sorting Complexes Required for Transport
  • Gene Expression Regulation / drug effects
  • Green Fluorescent Proteins
  • Humans
  • Interferon-gamma / pharmacology
  • Interleukin-2 / pharmacology
  • Intracellular Signaling Peptides and Proteins*
  • Jurkat Cells
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Lymphocyte Activation / drug effects
  • Phosphoproteins / genetics
  • Phosphoproteins / physiology*
  • RNA, Messenger / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Serine Endopeptidases*
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / metabolism
  • Th1 Cells / drug effects
  • Th1 Cells / metabolism
  • Th2 Cells / drug effects
  • Th2 Cells / metabolism
  • Transfection
  • Transforming Growth Factor beta / pharmacology*
  • Transforming Growth Factor beta1


  • Allergens
  • Antibodies
  • CD28 Antigens
  • CD3 Complex
  • Carrier Proteins
  • Endosomal Sorting Complexes Required for Transport
  • Interleukin-2
  • Intracellular Signaling Peptides and Proteins
  • Luminescent Proteins
  • Phosphoproteins
  • RNA, Messenger
  • Recombinant Fusion Proteins
  • TGFB1 protein, human
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • hepatocyte growth factor-regulated tyrosine kinase substrate
  • Green Fluorescent Proteins
  • Interferon-gamma
  • ZFYVE16 protein, human
  • Serine Endopeptidases