Molecular Genetics of T Cell Development

Abstract

■ Abstract T cell development is guided by a complex set of transcription factors that act recursively, in different combinations, at each of the developmental choice points from T-lineage specification to peripheral T cell specialization. This review describes the modes of action of the major T-lineage-defining transcription factors and the signal pathways that activate them during intrathymic differentiation from pluripotent precursors. Roles of Notch and its effector RBPSuh (CSL), GATA-3, E2A/HEB and Id proteins, c-Myb, TCF-1, and members of the Runx, Ets, and Ikaros families are critical. Less known transcription factors that are newly recognized as being required for T cell development at particular checkpoints are also described. The transcriptional regulation of T cell development is contrasted with that of B cell development, in terms of their different degrees of overlap with the stem-cell program and the different roles of key transcription factors in gene regulatory networks leading to lineage commitment. OVERVIEW OF T CELL DEVELOPMENT AND ITS REQUIREMENTST cells are the only hematopoietic cells that are not generated in the bone marrow. Instead, virtually all circulating T lymphocytes are generated in the thymus, and many different types exist. T cells are further distinguished among hematopoietic cells by their potentially infinite proliferative life spans and by their capacity for differentiative specialization even after their mature features are in place. Some of this specialization is triggered by environmental signals from antigen recognition and/or other ligand/receptor interactions. Thus T cell development, as a process, incorporates multiple stages at which different choices are available to the cells, extending over many cell cycles and a long period of time. In spite of this complexity, the T cell program as a whole is unified by the identities of the key regulators throughout the process: Many of the same regulatory factors and growth factor receptors are used again and again at different stages. This review focuses on the roles of these factors in establishing T cell identity as they guide uncommitted hematopoietic precursors into, and through, thymic differentiation. ROTHENBERG TAGHON A Map of the Terrain: Stages of T Cell DevelopmentAt least five stages have been defined in which specific regulators are needed for T cell development to proceed. First, there is the specification process, through which multipotent precursors first enter the T cell pathway, usually as they first immigrate to the thymus. Second is the complex process in which proliferative expansion and T cell receptor (TCR) gene rearrangement are combined with commitment to the T lineage within the thymus. These first stages are examined closely at the end of this review. Third is β-selection, which is a cascade of differentiation and proliferation events triggered specifically by "pre-TCR" signaling in precursors of TCRαβ T cells, after successful rearrangement of the TCRβ gene. Fourth is TCR-dependent positive selectio...

Downregulation of the transcription factor KLF4 is required for the lineage commitment of T cells

“…DN2 cells are able to differentiate into two different T cell lineages, namely, αβ T cells and γδ T cells [3,21]. To determine if enforced expression of Klf4 also impairs the generation of γδ T cells, we performed flow cytometry analysis of CD4 − CD8 − DN cells and observed a reduction of γδ T cells in Klf4Tg mice (Figure 4B and 4D).…”

Notch and Wnt signaling in T-lymphocyte development and acute lymphoblastic leukemia

“…The proliferation, differentiation and TCR rearrangement steps are tightly regulated by a number of molecular pathways (recently reviewed by Rothenberg and Taghon 16 ) of which Notch and Wnt signaling are perhaps the most conspicious.…”

Peripheral T Cell Lymphopenia and Concomitant Enrichment in Naturally Arising Regulatory T Cells: The Case of the Pre-Tα Gene-Deleted Mouse

“…Rare, multipotent progenitor cells having entered the thymus receive signals via Notch and cytokine receptors that both focus their commitment toward the T cell lineage and support their considerable proliferation (2). For T cells that will eventually express the ␣␤TCR, an early critical stage in their development involves successful rearrangements of TCR␤ genes and expression of a TCR␤ protein on the cell surface in association with a preexisting protein called pre-T␣ (pT␣) 4 (3).…”