Precursors entering the T-cell developmental pathway traverse a progression of states characterized by distinctive patterns of gene expression. Of particular interest are regulatory genes, which ultimately control the dwell time of cells in each state and establish the mechanisms that propel them forward to subsequent states. Under particular genetic and developmental circumstances, the transitions between these states occur with different timing, and environmental feedbacks may shift the steady-state accumulations of cells in each state. The fetal transit through pro-T cell stages is faster than in the adult, and subject to somewhat different genetic requirements. To explore causes of such variation, this review presents previously unpublished data on differentiation gene activation in pro-T cells of pre-TCR deficient mutant mice, and a quantitative comparison of the profiles of transcription factor gene expression in pro-T cell subsets of fetal and adult wildtype mice. Against a background of consistent gene expression, several regulatory genes show marked differences between fetal and adult expression profiles, including those encoding two bHLH antagonist Id factors, the Ets family factor SpiB, and the Notch target gene Deltex1. The results also reveal global differences in regulatory alterations triggered by the first TCR-dependent selection events in fetal and adult thymopoiesis. SEPARATE STAGES OF THE T-LINEAGE COMMITMENT PROCESS Regulatory requirements: the basic checklistAs hematopoietic multipotent progenitors work their way towards T cell differentiation, they shed other developmental options in a gradual process of T-lineage commitment. Accompanying the commitment process is what can be called the "specification" process, that is, the positive regulation of T-cell gene expression as the cells begin to adopt T-lineage characteristics. Both the positive events that promote T-lineage gene expression and the negative processes that block alternative fates are driven by shifting combinations of transcription factors that propagate new gene-expression and developmental states through successive cell cycles. Immunol Rev. 2006 February ; 209: 212-236. doi:10.1111/j.0105-2896.2006.00355.x. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThere has been a great deal of progress in the past few years identifying the regulatory inputs that guide T-lineage differentiation (rev. by (1;2); and see M. K. Anderson review, this volume). In general, pro-T cell emergence depends on at least nine different kinds of regulatory contributions, schematically shown in Fig. 1. These come from E2A and HEB bHLH transcription factors, Runx family transcription factors, transcription factor GATA-3, transcription factor c-Myb, Ikaros-type zinc finger family transcription factors, and TCF-1/ LEF-1 HMG box transcription factors activated by β-(or γ-) catenin. An early, hit and run function provided by the Ets family transcription factor PU.1 is also important for establishing the pro-T cell compartment....