ICAT expression disrupts beta-catenin-TCF interactions and impairs survival of thymocytes and activated mature T cells.
T cell factor (TCF) family of transcription factors and beta-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 beta-catenin, a major TCF cofactor, remains controversial. To directly address this, we have generated transgenic mice expressing Inhibitor of beta-catenin and TCF (ICAT), a naturally occurring inhibitor that specifically disrupts TCF and beta-catenin interactions. In this report, we demonstrate that disrupting the interaction of beta-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 beta-catenin. Indeed, we demonstrate that expression of ICAT impedes thymocyte survival by reducing the expression of Bcl(xL) in thymocytes below a critical threshold. Survival of activated mature T cells was also impaired due to diminished expression of activation-induced Bcl(xL). Accordingly, expression of transgenic Bcl-2 rescued activated ICAT-Tg CD4 T cells from apoptosis. Thus, disruption of TCF-beta-catenin interactions specifically impairs the survival of thymocytes and activated T cells.
Lymphocyte Development Unit, Laboratory of Immunology, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
M Zulfiquer
MZ
Hossain
Qing
Q
Yu
Mai
M
Xu
Jyoti Misra
JM
Sen
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002452:Cell Count; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D016130:Immunophenotyping; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D012097:Repressor Proteins; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013489:Suppression, Genetic / Q000276:immunology; D051820:TCF Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D051020:bcl-X Protein / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C498785:Ctnnbip1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D012097:Repressor Proteins; D051820:TCF Transcription Factors; D014157:Transcription Factors; D051020:bcl-X Protein; D051176:beta Catenin