Deletion of the CD4 silencer element supports a stochastic mechanism of thymocyte lineage commitment

Abstract

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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Figure 1: Gene-targeting at the CD4 locus.
Figure 2: Expression of CD4 on lymph node T cells.
Figure 3: Mature DP thymocytes in CD4Δsil mice.
Figure 4: Mature DP T cells in CD4Δsil mice.
Figure 5: MHC class II–restriction of DP cells.
Figure 6: Mature DP thymocytes and lymph node T cells in CD4Δsil mice that lacked MHC class I.

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Acknowledgements

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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Correspondence to Amin Rahemtulla.

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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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