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Sustained Expression of Pre-TCR Induced β-Catenin in Post-β-Selection Thymocytes Blocks T Cell Development¹

Mai Xu^*, Archna Sharma^*, M. Zulfiquer Hossain^*, David L. Wiest and Jyoti Misra Sen^2,*

^* Lymphocyte Development Unit, Laboratory of Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224; and Fox Chase Cancer Center, Division of Basic Sciences, Philadelphia, PA 19111

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 RORt, 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.

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 research was supported by the Intramural Research Program of the National Institute on Aging at the National Institutes of Health.

² Address correspondence and reprint requests to Jyoti Misra Sen, National Institute on Aging-National Institutes of Health, 08C218, Biomedical Research Center, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224. E-mail address: Jyoti-Sen{at}NIH.GOV

³ Abbreviations used in this paper: DP, double positive; DN, double negative; Egr, early growth response; Tg, transgenic; KO, knockout; TCRβ_IC, intracellular TCRβ; OIS, oncogene-induced senescence.