Stage-specific and differential notch dependency at the αβ and γδ T lineage bifurcation

Signals transduced by Notch receptors are indispensable for T cell specification and differentiation of up T lineage cells. However, the role of Notch signals during alpha beta versus gamma delta T lineage decision remains controversial. Here, we addressed this question by employing a clonal analysis of CD4(-)CD8(-) (DN) progenitor potential to position the divergence of alpha beta and gamma delta T cell lineages to the late DN2 to DN3 developmental stages. Accordingly, alpha beta and gamma delta precursor frequencies within these T cell progenitor subsets were determined, both in the presence and absence of Notch signaling through Delta-like 1. Notch signals were found to be critical for the DN to CD4(+)CD8(+) (DP) transition, irrespective of the identity (pT alpha beta or gamma delta) of the inducing T cell receptor complex, whereas gamma delta T cells developed from gamma delta TCR-expressing T cell progenitors in the absence of further Notch ligand interaction. Collectively, our findings demonstrate a differential, stage-specific requirement for Notch receptor-ligand interactions in the differentiation of up and gamma delta T cells from T cell progenitors.