MOLECULAR GENETICS OF T CELL DEVELOPMENT

Ellen V. Rothenberg, Tom Taghon
2005 Annual Review of Immunology  
■ 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,
more » ... h (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. 0732-0582/05/0423-0601$14.00 601 Annu. Rev. Immunol. 2005.23:601-649. Downloaded from arjournals.annualreviews.org by CALIFORNIA INSTITUTE OF TECHNOLOGY on 05/20/05. For personal use only. → Figure 1 Outline of T cell development: landmark stages, checkpoints, and developmental choices. Right side: cell-surface markers used in combination to distinguish specific developmental stages. DN: double negative for CD4 and CD8, and as used in this figure, implied to be negative for cell-surface T cell receptor complex expression as well. TCRγ δ and NKT cells are also commonly CD4 − CD8 − but are mature TCR + subsets that are presented separately. DN1, DN2, DN3, and DN4 stages of DN cell differentiation are distinguished by CD44, c-Kit, and CD25 expression as indicated. DP: CD4 + CD8 + TCRαβ-low. CD4 SP: CD4 + CD8 − TCRαβ-high. CD8 SP: CD4 − CD8 + TCRαβ-high. Branch points from the TCRαβ mainstream for NKT and T-reg lineages of TCRαβ cells are incompletely defined. Annu. Rev. Immunol. 2005.23:601-649. Downloaded from arjournals.annualreviews.org by CALIFORNIA INSTITUTE OF TECHNOLOGY on 05/20/05. For personal use only. REGULATION OF T CELL DEVELOPMENT 603 Annu. Rev. Immunol. 2005.23:601-649. Downloaded from arjournals.annualreviews.org by CALIFORNIA INSTITUTE OF TECHNOLOGY on 05/20/05. For personal use only. Critical Regulators: Introductory Overview Gene knockout experiments have shown that T cell development depends from its earliest stages on at least a half dozen transcription factors, one "instructive" Annu. Rev. Immunol. 2005.23:601-649. Downloaded from arjournals.annualreviews.org by CALIFORNIA INSTITUTE OF TECHNOLOGY on 05/20/05. For personal use only. REGULATION OF T CELL DEVELOPMENT 605 signaling system, and at least three other signaling systems used for growth and survival at particular points. Nearly all of these regulators play ongoing roles in T cell development, although their specific effects shift from one stage to another. They are introduced briefly here, and in the following sections, the roles of each of the transcriptional regulators are discussed in detail. T cell gene expression and even the first recognizable stages of T cell development depend on the transcription factors GATA-3, c-Myb, members of the Runx family, members of the E2A/HEB family, and members of the Ikaros family. In fetal life, appearance of specified pre-T cells also depends on the Ets-family transcription factor PU.1. Most of these factors are needed for other hematopoietic fates besides the T cell fate. Hunchback-class zinc finger factors of the Ikaros family are needed for all lymphocyte lineages, and the E2A/HEB class of bHLH transcription factors is absolutely essential for B cell development as well as for T cell development. Other factors, such as c-Myb, PU.1, and Runx1, are required to generate the multipotent hematopoietic progenitors of T cells, in addition to playing specific roles in early T cell functions proper. The one transcription factor that appears to be T cell specific is GATA-3. However, this too is a close relative of the stem-cell factor GATA-2. The ability of these molecules to turn on T cell genes as opposed to non-T cell genes is therefore likely to represent target-gene specificity emerging from combinatorial transcription factor action. T cell development also depends on two other transcription factors that represent dedicated effectors of cell-surface receptor signaling, TCF-1 (Tcf7) and RBPSuh (a.k.a. RBP-Jκ, or CBF/Suppressor of Hairless/Lag-1 = CSL). These factors are distinctive because they are repressors by default but are changed into activators by signaling cascades in response to environmental signals. TCF-1 is the effector of the Wnt/frz/β-catenin signaling cascade, and RBPSuh is the effector of the Notch signaling cascade. The exact roles that these factors play in T cell development appear to be different, as described below, but they share the critical feature that their presence in the precursors of T cells imposes a dichotomous switch-like behavior on every function they control. The same genes that they activate in the presence of a signal, they repress in the absence of a signal. The Notch signaling cascade is the unique "instructive" signaling system used for T cell specification, whereas the Wnt/TCF signaling system has an important role in proliferation coupled with differentiation. Other genes that are essential for T cell development encode cytokine receptors as well as pre-TCR/TCR components that are needed for survival and proliferation. Early in T cell development the IL-7 receptor complex (IL7Rα/γ c = CD127/CD132) is most important, while survival and proliferation are dominated later by signals from different versions of the TCR complex (pre-TCR, TCRγ δ, or TCRαβ associated with CD4 or CD8 coreceptors). These signal-dependent receptors all differ from the Notch system in that they primarily trigger the de novo appearance or nuclear localization of transcription factors, rather than conversion of a repressor to an activator. They thus lend themselves more to promoting graded responses, such as proliferation and activation, rather than the kinds of all-or-none Annu. Rev. Immunol. 2005.23:601-649. Downloaded from arjournals.annualreviews.org by CALIFORNIA INSTITUTE OF TECHNOLOGY on 05/20/05. For personal use only. Annu. Rev. Immunol. 2005.23:601-649. Downloaded from arjournals.annualreviews.org by CALIFORNIA INSTITUTE OF TECHNOLOGY on 05/20/05. For personal use only. Annu. Rev. Immunol. 2005.23:601-649. Downloaded from arjournals.annualreviews.org by CALIFORNIA INSTITUTE OF TECHNOLOGY on 05/20/05. For personal use only.
doi:10.1146/annurev.immunol.23.021704.115737 pmid:15771582 fatcat:5l2j6r5awzgd5mdgktwaqhkt7m