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 Blood, 1 April 2007, Vol. 109, No. 7, pp. 2944-2952.
Prepublished online as a Blood First Edition Paper on December 12, 2006; DOI 10.1182/blood-2006-03-006510.

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IMMUNOBIOLOGY

Twisted gastrulation (Tsg) is regulated by Tob and enhances TGF-ß signaling in activated T lymphocytes

Dimitrios Tzachanis1, Lequn Li2, Esther M. Lafuente2, Alla Berezovskaya3, Gordon J. Freeman3, and Vassiliki A. Boussiotis2,4

1 Department of Hematology and Oncology, Beth Israel–Deaconess Medical Center, Boston, MA; 2 Transplantation Biology Research Center, Massachusetts General Hospital, Boston; 3 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; 4 Department of Hematology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston

Quiescent T cells express Tob, an APRO gene family member, which functions as a transcriptional regulator. Subtractive hybridization identified Twisted gastrulation (Tsg) as one of the genes suppressed by Tob. Tsg is a secreted protein that interacts with Drosophila decapentaplegic (Dpp) and its vertebrate orthologs BMP2/4 and regulates morphogenetic effects in embryos. Here, we report the expression and function of Tsg in human T cells. Tsg mRNA was almost undetectable in unstimulated T cells and was up-regulated after activation by TCR/CD3 and either CD28, IL-2, or PMA. Tsg protein had no effect on responses of primary T cells to TCR/CD3 stimulation but had a potent inhibitory effect on proliferation and cytokine production of primed alloreactive CD4+ cells. Surprisingly, Tsg did not affect phosphorylation of the BMP-specific Smad1 but induced phosphorylation of the TGF-ß–specific Smad2 and mediated DNA binding on Smad3/4 consensus-binding sites, suggesting that it acted downstream of TGF-ß. In vitro association assays revealed a direct interaction of Tsg and TGF-ß proteins. Thus, Tsg functions as an agonist synergizing with TGF-ß to inhibit T-cell activation. Modulation of Tsg signaling may represent a novel target for molecular intervention toward control of aberrant T-cell responses during ongoing graft-versus-host disease (GVHD) and autoimmune diseases.


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