Beta-catenin/Tcf determines the outcome of thymic selection in response to alphabetaTCR signaling.
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.
Kovalovsky
Damian
D
Molecular Oncology Research Institute, Tufts New England Medical Center, Boston, MA 02111, USA.
Yu
Yu
Y
Dose
Marei
M
Emmanouilidou
Anastasia
A
Konstantinou
Tassos
T
Germar
Kristine
K
Aghajani
Katayoun
K
Guo
Zhuyan
Z
Mandal
Malay
M
Gounari
Fotini
F
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*
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