Sustained expression of pre-TCR induced β-catenin in post-β-selection thymocytes blocks T cell development

Pre-TCR and IL-7R signals regulate β-selection of thymocytes and then must be down-regulated for further development. However, the molecular events that control down-regulation remain unknown. We and others have previously shown that β-catenin in cooperation with TCF regulates β-selection. In this paper, we demonstrate that β-catenin expression is stringently regulated by intrathymic signals, it is expressed at the highest levels in the pre-TCR signaled thymocytes, and is down-regulated in post-β-selection thymocytes. Pre-TCR-induced β-catenin regulates initial stages of pre-TCR signaling including expression of early growth response (Egr) genes but must be down-regulated to express RORγt, which is essential for maturation to the CD4⁺CD8⁺ double positive (DP) stage. Sustained expression of β-catenin results in the generation of IL-7R-, Egr-, and TGFβ-expressing pre-DP thymocytes that are blocked in development. These data are consistent with a model in which post-β-selection, pre-TCR-induced β-catenin expression must return to background levels for efficient transition to the DP stage.