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SARA and Hgs attenuate susceptibility to TGF‐β 1‐mediated T cell suppression
Author(s) -
Kunzmann S.,
Wohlfahrt J. G.,
Itoh S.,
Asao H.,
Komada M.,
Akdis C. A.,
Blaser K.,
SchmidtWeber C. B.
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0550com
Subject(s) - smad , t cell , cd28 , transforming growth factor , receptor , microbiology and biotechnology , biology , transforming growth factor beta , cytotoxic t cell , cytokine , chemistry , endocrinology , immune system , immunology , in vitro , biochemistry
Transforming growth factor‐βl (TGF‐βl) 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‐β1 signaling. Both molecules are known to present Smad2 and Smad3 to the TGF‐β receptor complex. The role of SARA and Hgs in TGF‐β 1 susceptibility of human CD4 + T cells is unclear. We demonstrate here that TGF‐β1 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‐β1 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‐β1 susceptibility in T cells and integrate regulatory signals into the influence of TGF‐β 1‐mediated suppression of human T cells.—Kunzmann, S., Wohlfahrt, J. G., Itoh, S., Asao, H., Komada, M., Akdis, C. A., Blaser, K., Schmidt‐Weber, C. B. SARA and Hgs attenuate susceptibility to TGF‐β1‐mediated T cell suppression. FASEB J . 17, 194‐202 (2003)