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βTCR Signaling1
* Molecular Oncology Research Institute, Tufts New England Medical Center, Boston, MA 02111; and
Department of Medicine, Section of Rheumatology University of Chicago, Chicago, IL 60637
Thymic maturation of T cells depends on the intracellular interpretation of 
βTCR signals by processes that are poorly understood. In this study, we report that β-catenin/Tcf signaling was activated in double-positive thymocytes in response to βTCR engagement and impacted thymocyte selection. TCR engagement combined with activation of β-catenin signaled thymocyte deletion, whereas Tcf-1 deficiency rescued from negative selection. Survival/apoptotis mediators including Bim, Bcl-2, and Bcl-xL were alternatively influenced by stabilization of β-catenin or ablation of Tcf-1, and Bim-mediated β-catenin induced thymocyte deletion. TCR activation in double-positive cells with stabilized β-catenin triggered signaling associated with negative selection, including sustained overactivation of Lat and Jnk and a transient activation of Erk. These observations are consistent with β-catenin/Tcf signaling acting as a switch that determines the outcome of thymic selection downstream the βTCR cascade.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institute of Health Grants R01 AI059676-01 and R21 AI076720, American Cancer Society Grant LIB-113428, the Smith Family New Investigator Award from the Medical Foundation, and the GRASP Center P30 DK-34928 Award to F.G. Ruth L. Kirschstein National Research Service Award Institutional Research Training Grant T32 was awarded to D.K.
2 These authors have contributed equally to the publication.
3 Current address: Laboratory of T Cell Immunobiology, Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
4 Current address: MIT Center for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.
5 Address correspondence and reprint requests to Dr. Fotini Gounari, Department of Medicine, Section of Rheumatology University of Chicago, Chicago, IL 60637. E-mail address: fgounari{at}uchicago.edu
6 Abbreviations used in this paper: DP, double positive; DN, double negative; FDG, fluorescein-di-β-D-galactopyranoside; GSK-3β, glycogen synthase kinase-3β; HA, hemagglutinin; MFI, mean fluorescence intensity; MHCII, MHC class II; PKC, protein kinase C; SP, single positive.
7 The online version of this article contains supplemental material.
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