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International Immunology Advance Access originally published online on May 28, 2008
International Immunology 2008 20(7):925-935; doi:10.1093/intimm/dxn051
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Published by Oxford University Press 2008.

ICAT expression disrupts β-catenin–TCF interactions and impairs survival of thymocytes and activated mature T cells

M. Zulfiquer Hossain, Qing Yu, Mai Xu and Jyoti Misra Sen*

Lymphocyte Development Unit, Laboratory of Immunology, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA

* Correspondence to: J. M. Sen; E-mail: Jyoti-Sen{at}NIH.GOV

T cell factor (TCF) family of transcription factors and β-catenin critically regulate T cell development as demonstrated by the deletion of the tcf gene, which results in a block early in development that becomes complete in mice bearing tcf/lef double deletion. However, the role of β-catenin, a major TCF cofactor, remains controversial. To directly address this, we have generated transgenic mice expressing Inhibitor of β-catenin and TCF (ICAT), a naturally occurring inhibitor that specifically disrupts TCF and β-catenin interactions. In this report, we demonstrate that disrupting the interaction of β-catenin with TCF renders adult thymocytes and activated T cells highly susceptible to apoptosis. In contrast to previously reported observations during fetal thymocyte development, these data show that in adult mice, survival and not differentiation of thymocytes, depends on transcription by TCF and β-catenin. Indeed, we demonstrate that expression of ICAT impedes thymocyte survival by reducing the expression of BclxL in thymocytes below a critical threshold. Survival of activated mature T cells was also impaired due to diminished expression of activation-induced BclxL. Accordingly, expression of transgenic Bcl-2 rescued activated ICAT-Tg CD4 T cells from apoptosis. Thus, disruption of TCF-β-catenin interactions specifically impairs the survival of thymocytes and activated T cells.

Keywords: apoptosis, β-catenin, TCF, ICAT, thymus

Transmitting editor: C. Terhorst

Received 13 December 2007, accepted 23 April 2008.


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