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Differential synergy of Notch and T cell receptor signaling determines αβ versus γδ lineage fate

Differential synergy of Notch and T cell receptor signaling determines αβ versus γδ lineage fate Thymic precursors expressing the pre–T cell receptor (TCR), the γδTCR, or the αβTCR can all enter the CD4 + 8 + αβ lineage, albeit with different efficacy. Here it is shown that proliferation and differentiation of precursors with the different TCRs into αβ lineage cells require Notch signaling at the DN3 stage of thymic development. At the DN4 stage, Notch signaling still significantly contributes to the generation of αβ T cells. In particular, in αβ lineage commitment, the pre-TCR synergizes more efficiently with Notch signals than the other two TCRs, whereas γδTCR-expressing cells can survive and expand in the absence of Notch signals, even though Notch signaling enhances their proliferation. These observations suggest a new model of αβ versus γδ lineage choice in which lineage fate is determined by the extent of synergy between TCR and Notch signaling and in which the evolutionarily recent advent of the cell-autonomously signaling pre-TCR increased the efficacy of αβ T cell generation. Footnotes Abbreviations used: DL-1, Delta-like 1; DN, double negative; DP, double positive; GSI, γ-secretase inhibitor; pTα, pre-TCRα. A.I. Garbe and A. Krueger contributed equally to this work. Submitted: 1 March 2006 Accepted: 9 May 2006 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Experimental Medicine Rockefeller University Press

Differential synergy of Notch and T cell receptor signaling determines αβ versus γδ lineage fate

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Publisher
Rockefeller University Press
Copyright
© 2006 Rockefeller University Press
ISSN
0022-1007
eISSN
1540-9538
DOI
10.1084/jem.20060474
pmid
16754723
Publisher site
See Article on Publisher Site

Abstract

Thymic precursors expressing the pre–T cell receptor (TCR), the γδTCR, or the αβTCR can all enter the CD4 + 8 + αβ lineage, albeit with different efficacy. Here it is shown that proliferation and differentiation of precursors with the different TCRs into αβ lineage cells require Notch signaling at the DN3 stage of thymic development. At the DN4 stage, Notch signaling still significantly contributes to the generation of αβ T cells. In particular, in αβ lineage commitment, the pre-TCR synergizes more efficiently with Notch signals than the other two TCRs, whereas γδTCR-expressing cells can survive and expand in the absence of Notch signals, even though Notch signaling enhances their proliferation. These observations suggest a new model of αβ versus γδ lineage choice in which lineage fate is determined by the extent of synergy between TCR and Notch signaling and in which the evolutionarily recent advent of the cell-autonomously signaling pre-TCR increased the efficacy of αβ T cell generation. Footnotes Abbreviations used: DL-1, Delta-like 1; DN, double negative; DP, double positive; GSI, γ-secretase inhibitor; pTα, pre-TCRα. A.I. Garbe and A. Krueger contributed equally to this work. Submitted: 1 March 2006 Accepted: 9 May 2006

Journal

The Journal of Experimental Medicine – Rockefeller University Press

Published: Jun 12, 2006

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