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 gamma delta TCR, or the alpha beta TCR can all enter the CD(4+)8(+) alpha beta lineage, albeit with different efficacy. Here it is shown that proliferation and differentiation of precursors with the different TCRs into alpha beta 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 beta T cells. In particular, in alpha beta 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 beta 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 beta T cell generation.