TCR and Notch synergize in αβ versus γδ lineage choice

At two checkpoints, T cell development is controlled by T cell receptor (TCR) signaling, which determines survival and lineage commitment. At the first of these checkpoints, signaling by the pre-TCR, the γδTCR or the αβTCR has a major but nonexclusive impact on whether cells will become CD4−CD8− γδ or CD4+CD8+ αβ lineage cells. Pre-TCR signals synergize with moderate Notch signals to generate αβ lineage cells. Relatively strong signals by the γδTCR (or early expressed αβTCR) in the absence of Notch signaling are sufficient to yield γδ lineage cells. However, relatively weak signals of the latter two receptors combined with strong Notch signaling result in the formation of αβ lineage cells that generate a diverse αβTCR repertoire in pre-TCR-deficient mice. It remains to be determined whether TCR and/or Notch signals instruct or confirm predetermined lineage fate.