title: Beta-catenin/Tcf determines the outcome of thymic selection in response to alphabetaTCR signaling.
abstract: Thymic maturation of T cells depends on the intracellular interpretation of alphabetaTCR signals by processes that are poorly understood. In this study, we report that beta-catenin/Tcf signaling was activated in double-positive thymocytes in response to alphabetaTCR engagement and impacted thymocyte selection. TCR engagement combined with activation of beta-catenin signaled thymocyte deletion, whereas Tcf-1 deficiency rescued from negative selection. Survival/apoptotis mediators including Bim, Bcl-2, and Bcl-x(L) were alternatively influenced by stabilization of beta-catenin or ablation of Tcf-1, and Bim-mediated beta-catenin induced thymocyte deletion. TCR activation in double-positive cells with stabilized beta-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 beta-catenin/Tcf signaling acting as a switch that determines the outcome of thymic selection downstream the alphabetaTCR cascade.
authors.affiliation: Molecular Oncology Research Institute, Tufts New England Medical Center, Boston, MA 02111, USA.
authors.forename: Damian
authors.initials: D
authors.lastname: Kovalovsky
authors.forename: Yu
authors.initials: Y
authors.lastname: Yu
authors.forename: Marei
authors.initials: M
authors.lastname: Dose
authors.forename: Anastasia
authors.initials: A
authors.lastname: Emmanouilidou
authors.forename: Tassos
authors.initials: T
authors.lastname: Konstantinou
authors.forename: Kristine
authors.initials: K
authors.lastname: Germar
authors.forename: Katayoun
authors.initials: K
authors.lastname: Aghajani
authors.forename: Zhuyan
authors.initials: Z
authors.lastname: Guo
authors.forename: Malay
authors.initials: M
authors.lastname: Mandal
authors.forename: Fotini
authors.initials: F
authors.lastname: Gounari
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D051538:Hepatocyte Nuclear Factor 1-alpha; D051379:Mice; D018345:Mice, Knockout; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D051822:T Cell Transcription Factor 1 / Q000172:deficiency / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology* / Q000502:physiology; D051176:beta Catenin / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; D016693:Receptors, Antigen, T-Cell, alpha-beta; D051822:T Cell Transcription Factor 1; D051176:beta Catenin