Submitted March 1, 2006
Accepted November 14, 2006
Twisted Gastrulation (Tsg) is regulated by Tob and enhances TGF-
signaling in activated T lymphocytes
Dimitrios Tzachanis, Lequn Li, Esther M Lafuente, Alla Berezovskaya, Gordon J. Freeman, and Vassiliki A. Boussiotis*
Dept of Hematology & Oncology, Beth Israel-Deaconess Medical Center, Boston, MA, United States
Transplantation Biology Research Center, Massachusetts General Hospital, Boston, MA, United States
Dept of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
Dept of Hematology & Oncology, Massachusetts General Hospital, Boston, MA, United States
* Corresponding author; email: vboussiotis{at}partners.org.
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 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 upregulated 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-
-specific Smad2 and mediated DNA binding on Smad3/4 consensus binding sites, suggesting that acted downstream of TGF-. In vitro association assays revealed a direct interaction of Tsg and TGF- proteins. Thus Tsg functions as an agonist synergizing with TGF- to inhibit T cell activation. Modulation of Tsg signaling may represent a novel target for molecular intervention towards control of aberrant T cell responses during ongoing GVHD and autoimmune diseases.
