β-Selection-Induced Proliferation Is Required for αβ T Cell Differentiation

SummaryProliferation and differentiation are tightly coordinated to produce an appropriate number of differentiated cells and often exhibit an antagonistic relationship. Developing T cells, which arise in the thymus from a minute number of bone-marrow-derived progenitors, undergo a major expansion upon pre-T cell receptor (TCR) expression. The burst of proliferation coincides with differentiation toward the αβ T cell lineage—but the two processes were previously thought to be independent from one another, although both were driven by signaling from pre-TCR and Notch receptors. Here we report that proliferation at this step was not only absolutely required for differentiation but also that its ectopic activation was sufficient to substantially rescue differentiation in the absence of Notch signaling. Consistently, pharmacological inhibition of the cell cycle machinery also blocked differentiation in vivo. Thus the proliferation step is strictly required prior to differentiation of immature thymocytes.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (167 K)Download as PowerPoint slideHighlights► β-selection-induced proliferation is required for αβ T cell differentiation ► Proliferation partially rescues differentiation without Notch but not pre-TCR signaling ► Notch target Myc rescues differentiation in the absence of Notch signaling ► Transcription factor E47 imposes the dependence of differentiation on proliferation