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Swiss Institute of Allergy and Asthma Research (SIAF), CH-7270 Davos, Switzerland;
* Division of Cellular Biochemistry, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands;
Department of Microbiology and Immunology, Tohoku University School of Medicine, Aoba-ku, Sendai 980-8575 Japan; and
Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Midori-ku, Yokohama 226, Japan
1Correspondence: Swiss Institute of Allergy and Asthma Research (SIAF), Obere Str. 22, CH-7270 Davos, Switzerland. E-mail: csweber{at}siaf.unizh.ch
Transforming growth factor-ß1 (TGF-ß1) 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-ß1 signaling. Both molecules are known to present Smad2 and Smad3 to the TGF-ß receptor complex. The role of SARA and Hgs in TGF-ß1 susceptibility of human CD4+ T cells is unclear. We demonstrate here that TGF-ß1 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-ß1 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-ß1 susceptibility in T cells and integrate regulatory signals into the influence of TGF-ß1-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-ß1-mediated T cell suppression.
Key Words: SARA • Hgs • TGF-ß1 • CD4+ T cells • T cell tolerance • nucleofection
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