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Duration of TCR signaling controls CD4-CD8 lineage differentiation in vivo

Nature Immunology volume 5, pages 280–288 (2004)Cite this article

Abstract

The duration of T cell receptor (TCR) signaling is thought to be important for thymocyte differentiation into the CD4 or CD8 lineage. However, the in vivo relevance of this hypothesis is unclear. Here we divided T cell positive selection into genetically separable developmental steps by confining TCR signal transduction to discrete thymocyte developmental windows. TCR signals confined to the double-positive thymocyte stage promoted CD8, but not CD4, lineage differentiation. Major histocompatibility complex (MHC) class II–restricted thymocytes were, instead, redirected into the CD8 lineage. These findings support the hypothesis that distinct kinetics of MHC class I– and MHC class II–induced TCR signals direct intrathymic developmental decisions.

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Figure 1: Thymocyte populations in ADA-Zap70+/− and ADA-Zap70+/+ mice.
Figure 2: DP-confined TCR signaling enables CD8 lineage differentiation.
Figure 3: DP-confined TCR signaling fails to promote CD4 lineage differentiation.
Figure 4: DP-confined TCR signaling redirects MHC class II–restricted thymocytes into the CD8 lineage.
Figure 5: Extending the survival of ADA-Zap70+/− thymocytes restores CD8 SP thymocyte populations.
Figure 6: CD5 disruption in ADA-Zap70+/− mice extends the developmental window of TCR signals transduction and restores CD4 lineage differentiation.

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Acknowledgements

We thank L. Samelson, P. Ohashi, A. Tarakhovsky for mice and reagents; A. Singer for mice and for support of the initial phases of this project; A. Adams, L. Granger and B. Taylor for flow cytometry; K. Wildt for technical assistance; G. Sanchez and P. Mercado for animal care and assistance with mouse genotyping; A. Bhandoola and A. Singer for discussions; and J. Ashwell, A. Bhandoola, A. Gegonne, P. Schwartzberg and A. Singer for critical reading of the manuscript.

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  1. Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Xiaolong Liu & Rémy Bosselut

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Correspondence to Rémy Bosselut.

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Liu, X., Bosselut, R. Duration of TCR signaling controls CD4-CD8 lineage differentiation in vivo. Nat Immunol 5, 280–288 (2004). https://doi.org/10.1038/ni1040

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