The Journal of Experimental Medicine
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Published online 5 June 2006 doi:10.1084/jem.20060474
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 6, 1579-1590
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ARTICLE

 Differential synergy of Notch and T cell receptor signaling determines {alpha}ß versus {gamma}{delta} lineage fate

Annette I. Garbe1, Andreas Krueger1, Fotini Gounari1,2, Juan Carlos Zúñiga-Pflücker3, and Harald von Boehmer1

1 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115
2 Tufts-New England Medical Center, Boston, MA 02111
3 University of Toronto, Toronto, Ontario, M4N 3M5 Canada

CORRESPONDENCE Harald von Boehmer: Harald_von_Boehmer{at}dfci.harvard.edu

Thymic precursors expressing the pre–T cell receptor (TCR), the {gamma}{delta}TCR, or the {alpha}ßTCR can all enter the CD4+8+ {alpha}ß lineage, albeit with different efficacy. Here it is shown that proliferation and differentiation of precursors with the different TCRs into {alpha}ß 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 {alpha}ß T cells. In particular, in {alpha}ß lineage commitment, the pre-TCR synergizes more efficiently with Notch signals than the other two TCRs, whereas {gamma}{delta}TCR-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 {alpha}ß versus {gamma}{delta} 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 {alpha}ß T cell generation.

Abbreviations used: DL-1, Delta-like 1; DN, double negative; DP, double positive; GSI, {gamma}-secretase inhibitor; pT{alpha}, pre-TCR{alpha}.

A.I. Garbe and A. Krueger contributed equally to this work.


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