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KEY POINTS * T cell development depends on the regulated progression of progenitor cells through three major phases that are associated with distinct transcription factor ensembles and

altered gene regulatory network states. * The first two phases are Notch dependent and T cell receptor (TCR) independent, whereas the third phase is TCR dependent and mediates the transition

to Notch independence. * The first phase is dominated by legacy stem and progenitor cell gene regulatory networks that enable self-renewal and Notch-dependent expression of the first T

cell-specific transcription factors, including GATA-binding protein 3 (GATA3) and T cell factor 1 (TCF1). * T cell lineage commitment — the loss of alternative latent developmental

potentials — is triggered by induction of the phase 2 transcription factor B cell lymphoma–leukaemia 11B (BCL11B) and results in the downregulation of multiple progenitor-specific

transcription factors. * In phase 2, T cell-specific regulators and Notch signalling drive the full activation of the T cell gene regulatory programme. TCR complex signalling components are

expressed, TCR gene recombination is induced and TCR-dependent selection thresholds are imposed. * Transition from phase 2 to phase 3 depends on the expression and successful signalling of a

pre-TCR or γδTCR. If successful, this switch from the phase 2 to phase 3 network triggers proliferation, loss of Notch dependency and dismantling of the Notch-dependent gene network. *

Phase 1 legacy and stem cell transcription factors can become oncogenic if their expression is not correctly controlled. Cells that fail to fully shut off the expression of phase 1

regulators at the commitment and β-selection checkpoints — before the next phase of gene network expression is activated — may be predisposed to leukaemic transformation. ABSTRACT Cells

acquire their ultimate identities by activating combinations of transcription factors that initiate and sustain expression of the appropriate cell type-specific genes. T cell development

depends on the progression of progenitor cells through three major phases, each of which is associated with distinct transcription factor ensembles that control the recruitment of these

cells to the thymus, their proliferation, lineage commitment and responsiveness to T cell receptor signals, all before the allocation of cells to particular effector programmes. All three

phases are essential for proper T cell development, as are the mechanisms that determine the boundaries between each phase. Cells that fail to shut off one set of regulators before the next

gene network phase is activated are predisposed to leukaemic transformation. Access through your institution Buy or subscribe This is a preview of subscription content, access via your

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* Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS RUNX FACTORS LAUNCH T CELL AND INNATE LYMPHOID PROGRAMS VIA DIRECT

AND GENE NETWORK-BASED MECHANISMS Article 10 August 2023 HOW TRANSCRIPTION FACTORS DRIVE CHOICE OF THE T CELL FATE Article 11 September 2020 T-CELL COMMITMENT INHERITANCE—AN AGENT-BASED

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1091–1094 (2008). CAS  Google Scholar  Download references ACKNOWLEDGEMENTS The authors apologize to colleagues whose work helped to inspire this Review but could not be cited due to space

constraints. The authors thank present and former members of their group whose published and unpublished data, as well as helpful discussion, shaped the ideas presented here. The authors

gratefully acknowledge support from the US National Institutes of Health (NIH grant AI064590 to M.A.Y., and AI083514, AI095943 and HD076915 to E.V.R.) and the Albert Billings Ruddock

Professorship (to E.V.R). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Division of Biology 156–29, California Institute of Technology, Pasadena, 91125, California, USA Mary A. Yui & 

Ellen V. Rothenberg Authors * Mary A. Yui View author publications You can also search for this author inPubMed Google Scholar * Ellen V. Rothenberg View author publications You can also

search for this author inPubMed Google Scholar ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. RELATED LINKS FURTHER INFORMATION ImmGen

POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1 POWERPOINT SLIDE FOR FIG. 2 POWERPOINT SLIDE FOR FIG. 3 POWERPOINT SLIDE FOR TABLE 1 POWERPOINT SLIDE FOR TABLE 2 SUPPLEMENTARY INFORMATION

SUPPLEMENTARY INFORMATION S1 (TABLE) Critical T cell specification transcription factor genes in murine early T cells and their progenitors (PDF 638 kb) SUPPLEMENTARY INFORMATION S2 (TABLE)

Critical phase 1-specific transcription factor genes in murine early T cells and their progenitors (PDF 633 kb) GLOSSARY * Commitment The stage at which cells give up their intrinsic

capability to produce more than one kind of descendant. This concept depends on recognizing that precursor cells begin with the intrinsic potential to give rise to various different types of

descendant, but the actual fate choices that such precursor cells adopt will be different depending on the signals that they receive from the environment. Commitment is the developmental

transition within a given pathway during which the chosen cell fate becomes intrinsically irreversible, independent of the environment. * Gene regulatory network A system of relationships

between a set of regulatory genes and the transcription factors that they encode, which is defined such that the interactions between them explain the stability or change in the

developmental properties of a cell type that expresses those genes. * Notch signalling A signalling system comprised of highly conserved transmembrane receptors that regulate cell fate

choice in the development of many cell lineages and are thus crucial for the regulation of embryonic differentiation and development. Unusually among signalling systems, the cytoplasmic

domain of each Notch transmembrane protein can itself become a transcriptional co-activator in the nucleus, as it can be proteolytically cleaved from the transmembrane region when Notch

interacts with its ligands of the Delta or Jagged family. * T cell acute lymphoblastic leukaemia (T-ALL). Leukaemia with an immature T cell phenotype. * Common lymphoid precursors (CLPs).

These are a type of progenitor cell that seems to be committed to lymphoid fates (as measured by _in vivo_ transfer) and that can give rise to all lymphoid cell types, including T cells, B

cells and natural killer cells. * Lymphoid-primed multipotent precursors (LMPPs). These are multilineage precursor cells that can generate myeloid and lymphoid descendants _in vivo_ and _in

vitro_ but that cannot generate erythroid or megakaryocytic cells. * Positive selection A step in the process of T cell differentiation in the thymus that selects CD4+CD8+ double-positive T

cells for survival and maturation, on the basis of the appropriate degree of interaction between their T cell receptor and the peptide—MHC complexes that are expressed on thymic epithelial

cells. Depending on the class of MHC molecule that is recognized, thymocytes are positively selected to a CD4+ or a CD8+ single-positive cell fate. * Pioneer factor A transcription factor

that has the ability to bind to its target site even when the site is initially located within nucleosome-packed chromatin, thus serving as a focal point for the recruitment of other

transcription factors. Pioneer factors are crucial for the multi-step process that is needed to activate some positive regulatory elements in the genome during development. * WNT A

signalling mediator named both for its mutant phenotype in _Drosophila melanogaster_ (Wingless) and for its role as a preferential retrovirus integration site in murine leukaemia

virus-induced leukaemias (Int-1). WNT signalling activates the T cell factor 1 (TCF1) and lymphoid enhancer-binding factor 1 (LEF1) family transcription factors through stabilizing their

co-activator, β-catenin, and mobilizing it from the cytoplasm to the nucleus. * Chromatin immunoprecipitation followed by sequencing (ChIP–seq). A genome-wide method of mapping the sites at

which a transcription factor binds to the DNA in a cell, that involves crosslinking proteins to chromatin, immunoprecipitating the chromatin with antibodies specific for the factor of

interest, comprehensively sequencing the DNA that is recovered in the immunoprecipitates and aligning the obtained sequences with the genome to identify the enriched regions. * Non-obese

diabetic mice (NOD mice). These mice spontaneously develop type 1 (insulin-dependent) diabetes mellitus as a result of autoreactive T cell-mediated destruction of pancreatic β-islet cells.

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