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Sci. Signal., 23 March 2010
Vol. 3, Issue 114, p. ra23
[DOI: 10.1126/scisignal.2000702]

RESEARCH ARTICLES

Regulation of Zap70 Expression During Thymocyte Development Enables Temporal Separation of CD4 and CD8 Repertoire Selection at Different Signaling Thresholds

Manoj Saini1*{dagger}, Charles Sinclair1*, Daniel Marshall1, Mauro Tolaini2, Shimon Sakaguchi3, and Benedict Seddon1{ddagger}

1 Division of Immune Cell Biology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
2 Division of Molecular Immunology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
3 Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.

* These authors contributed equally to this work.

{dagger} Present address: MRC Centre for Immune Regulation, Division of Immunity and Infection, Birmingham University, Birmingham B15 2TT, UK.

Abstract: To investigate the temporal regulation of the commitment of immature thymocytes to either the CD4+ or the CD8+ lineage in the thymus, we developed a transgenic mouse that expressed a tetracycline-inducible gene encoding the tyrosine kinase {zeta} chain–associated protein kinase of 70 kD (Zap70), which restored development in Zap70–/– thymocytes arrested at the preselection, CD4+CD8+ double-positive (DP) stage. After induction of the expression of Zap70 and the production of Zap70 protein, CD4+ single-positive (SP) cells that expressed Zbtb7b (which encodes the CD4+ T cell–associated transcription factor ThPOK) became abundant within 30 hours, whereas CD8+ SP cells were not detectable until day 4. We found that mature CD4+ and CD8+ cells arose from phenotypically distinct subsets of DP thymocytes that developed with different kinetics and contrasting sensitivities to stimulation of the T cell antigen receptor (TCR). In wild-type mice, expression of endogenous Zap70 progressively increased during maturation of the DP subsets, and the abundance of Zap70 protein determined the sensitivity of the cells to stimulation of the TCR. This temporal gradient in the amount of Zap70 protein enabled the selection of CD4+ and CD8+ repertoires in separate temporal windows and at different TCR signaling thresholds, thereby facilitating discrimination of distinct positive selection signals in these lineages.

{ddagger} To whom correspondence should be addressed. E-mail: bseddon{at}nimr.mrc.ac.uk

Citation: M. Saini, C. Sinclair, D. Marshall, M. Tolaini, S. Sakaguchi, B. Seddon, Regulation of Zap70 Expression During Thymocyte Development Enables Temporal Separation of CD4 and CD8 Repertoire Selection at Different Signaling Thresholds. Sci. Signal. 3, ra23 (2010).

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