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TCR Silencing during T Cell Development Depends upon Pre-TCR-Induced Proliferation

Isabel Ferrero^*, Stéphane J. C. Mancini, Frederic Grosjean, Anne Wilson^*, Luc Otten and H. Robson MacDonald^1,*

^* Ludwig Institute for Cancer Research, Lausanne Branch, and Institute for Biochemistry, University of Lausanne, Lausanne, Switzerland; and Centre d’Immunologie de Marseille Luminy, Parc Scientifique de Luminy, Marseille, France

During thymus development, immature T cells become committed to two distinct lineages based upon expression of or TCR. In the lineage, developing thymocytes progressively extinguish transcription of the TCR genes by a poorly understood process known as silencing. We show that lineage thymocytes in mice lacking a functional pre-TCR undergo limited proliferation and fail to silence TCR genes during development. Stimulation of pre-TCR-deficient immature thymocytes with anti-CD3 Abs does not directly down-regulate TCR transcription but restores TCR silencing following proliferation. Collectively our data reveal an important role for pre-TCR induced proliferation in activating the TCR silencer in lineage thymocytes, a process that may reinforce or lineage commitment.

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 Address correspondence and reprint requests to Dr. H. Robson MacDonald, Ludwig Institute for Cancer Research, Lausanne Branch University of Lausanne, CH-1066 Epalinges, Switzerland. E-mail address: hughrobson.macdonald{at}isrec.unil.ch

² Abbreviations used in this paper: DN, double negative; DP, double positive; WT, wild type; ISP, immature single positive; ICER, inducible cAMP early repressor.

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