The mechanism of T cell lineage commitment remains controversial; to examine it we deleted the CD4-silencer element in the germ line of a mouse using a combination of gene targeting and Cre/LoxP-mediated recombination. We found that these mice were unable to extinguish CD4 expression either in immature thymocytes or mature CD8+ cytotoxic T cells (CTLs), which resulted in the development of major histocompatibility complex class II–restricted double-positive CTLs in the periphery. This finding strongly supports a stochastic over an instructive mechanism of coreceptor down-regulation.
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We thank H. Waldmann, R. Lechler and R. Zinkernagel for advice and helpful discussions; J. Rossant for the D3 embryonic stem cell line; K. Rajewski for the Cre-Lox cassettes; and R. Sumner and C. Hetherington for help with some blastocyst injections. Supported by the Croucher Foundation (R. L) and the Wellcome Trust (K. T and A. R).
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Leung, R., Thomson, K., Gallimore, A. et al. Deletion of the CD4 silencer element supports a stochastic mechanism of thymocyte lineage commitment. Nat Immunol 2, 1167–1173 (2001) doi:10.1038/ni733
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