Launching the T-cell-lineage developmental programme

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Abstract
The early, T-cell receptor (TCR)-independent stages of T-cell development are summarized in this Review. The process of specification, through which developing precursors gain T-cell characteristics, is paralleled by the process of commitment, through which they lose the potential to follow alternative developmental routes. Both of these processes now appear to occur in discrete steps, with an important transition within the double-negative 2 (DN2) stage. Notch signalling is important from entry of T-cell precursors into the thymus to the culmination of T-cell-lineage commitment many cell divisions later. However, the gene regulatory effects of Notch signalling differ from stage to stage, greatly affected by shifts in the activities of other transcription factors and by responses to other environmental signals. Detailed expression patterns of multiple differentiation and regulatory genes are shown. The initiation of the T-cell developmental programme by Notch signalling depends on the activity of at least four other transcription factors or transcription factor families which define the competence of pre-thymic precursors. Even when Notch signalling is under way, the differentiation of the early intrathymic precursors to the DN2 stage is controlled by a complex mixture of other microenvironmental signals and a newly defined negative feedback network for Notch itself. A core group of transcription factors collaborates with Notch repeatedly throughout early T-cell development to maintain or advance T-cell-lineage differentiation. These are not turned on de novo during commitment, but rather are expressed steadily or at gently increasing levels from the earliest intrathymic stage to commitment. Other, crucial but less well studied, transcription factors are more dynamically upregulated at developmental transition points. Another group of transcription factors, inherited from multipotent progenitors, is downregulated asynchronously and silenced during commitment. Factors in this non-T-cell-lineage class are apparently responsible for the lineage plasticity that early T-cell precursors retain for many cell generations within the thymus. One role of Notch signalling in vivo might be to constrain the lineage diversionary activities of this group of factors until they are permanently silenced. The commitment process and the unleashing of T-cell-lineage differentiation gene expression are both correlated with downregulation of the non-T-cell-lineage factors. A critical component of the T-cell commitment mechanism that remains to be discovered is the repressor or repressor network that silences these non-T-cell-lineage factors.

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