TOX Provides a Link Between Calcineurin Activation and CD8 Lineage Commitment

Aliahmad, Parinaz; O'Flaherty, E; Han, Peggy; Goularte, Olivia D.; Wilkinson, Beverley; Satake, Masanobu; Molkentin, Jeffery D.; Kaye, Jonathan

doi:10.1084/jem.20040051

Cited by 65 publications

(89 citation statements)

References 64 publications

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“…One such putative transcriptional regulator could be TOX, another bHLH transcription factor found upregulated by gene profiling in SS in this study (log 10 P46.3) that is known to be involved in thymocyte differentiation. 23 In summary, we have identified and validated marker genes differentially expressed by leukemic T cells in SS, including PLS3, DNM3, IGFL2, CDO1, TNFSF11, NEDD4L and KLHDC5. These genes well discriminate between peripheral blood mononuclear cells in SS as compared to healthy controls and ID.…”

Section: Discussionmentioning

confidence: 99%

Sézary syndrome is a unique cutaneous T-cell lymphoma as identified by an expanded gene signature including diagnostic marker molecules CDO1 and DNM3

et al. 2007

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Section: Discussionmentioning

confidence: 99%

Sézary syndrome is a unique cutaneous T-cell lymphoma as identified by an expanded gene signature including diagnostic marker molecules CDO1 and DNM3

et al. 2007

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“…However, inactivation of either of these genes fails to cause redirection of class-II-restricted cells to the CD8 lineage 26,28 , suggesting that they do not regulate the commitment process itself. Furthermore, transgenic overexpression of the nuclear high-mobility group (HMG) box protein TOX mediates development of thymocytes exclusively to the CD8 lineage 29 . However, this occurs only in the absence of TCR engagement, not when thymocytes receive normal TCR signals, arguing against a physiological role in lineage commitment 29,30 .…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, transgenic overexpression of the nuclear high-mobility group (HMG) box protein TOX mediates development of thymocytes exclusively to the CD8 lineage 29 . However, this occurs only in the absence of TCR engagement, not when thymocytes receive normal TCR signals, arguing against a physiological role in lineage commitment 29,30 .…”

Section: Discussionmentioning

confidence: 99%

The zinc finger transcription factor Th-POK regulates CD4 versus CD8 T-cell lineage commitment

Xiao

Davé

et al. 2005

Nature

360

448

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Development of immature T-cell precursors (thymocytes) to either the CD4 helper or CD8 killer T-cell lineages correlates precisely with their T-cell receptor specificity for major histocompatibility complex class II or class I molecules, respectively, indicating that the process is carefully regulated. Although intensively studied owing to its importance in determining the composition of the mature T-cell compartment and as a general model of binary lineage decisions, the underlying molecular pathways remain obscure. We have previously reported a spontaneous mouse mutant (HD (helper deficient) mice) in which lineage commitment is specifically perturbed without affecting positive selection. Here we show that a point mutation in the zinc finger transcription factor Th-POK (T-helper-inducing POZ/Krü ppel-like factor) is responsible for redirection of class-II-restricted thymocytes to the CD8 lineage in HD mice. Furthermore, we demonstrate that constitutive expression of this factor during thymic development leads to redirection of class-I-restricted thymocytes to the CD4 lineage, indicating that Th-POK is a master regulator of lineage commitment.Developing ab T cells progress through three major stages in the thymus, defined by differential expression of the CD4 and CD8 coreceptor molecules; that is, CD4 2 CD8 2 (double negative), CD4 þ CD8 þ (double positive) and CD4 þ CD8 2 or CD4 2 CD8 þ (single positive). The double-positive to single-positive transition depends on productive rearrangement of both a-and b-subunits of the T-cell receptor (TCR) and engagement of the complete ab TCR by intrathymic ligands (positive selection). Simultaneously, thymocytes diverge into the functionally distinct T-helper and T-killer lineages, defined by expression of CD4 and CD8, respectively. Mature T cells show an almost perfect correlation between CD4 or CD8 expression and their TCR specificity towards class II or class I major histocompatibility complex (MHC) molecules, respectively. Alternative instructive and stochastic/selective models have been proposed to explain this marked correlation (for recent reviews see refs 1, 2). Current thinking favours a quantitative version of the instructive model, whereby lineage choice is determined by the relative strength or duration of TCR engagement 3-9 ; however, the intracellular pathways that are involved remain unknown.Progress in the field has been hindered because lineage commitment is so intimately tied to the process of positive selection that it is difficult to study in isolation. Hence, no specific pathways have been identified that are required for lineage commitment but not positive selection. Recently, we identified a spontaneous recessive mutation in mice, the HD mutation, which appeared to identify a genetic locus specifically required for lineage commitment 10 . Notably, this mutation caused redirection of all class-II-restricted thymocytes to the CD8 lineage 11 . The existence of such a mutation demonstrated a mechanistic distinction between the pathways governing lineage ...

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“…TOX is specifically upregulated following pre-TCR signaling and positive selection, but, strikingly, does not seem to be involved in TCR-mediated activation of mature, peripheral T cells. (153). This cascade can be counteracted by strong or sustained TCR signaling, a process that involves upregulation of GATA-3.…”

Section: Tox: a New Hmg Box Factormentioning

confidence: 99%

Molecular Genetics of T Cell Development

Rothenberg

Taghon

2005

Annu. Rev. Immunol.

230

187

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■ 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...

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TOX Provides a Link Between Calcineurin Activation and CD8 Lineage Commitment

Cited by 65 publications

References 64 publications

Sézary syndrome is a unique cutaneous T-cell lymphoma as identified by an expanded gene signature including diagnostic marker molecules CDO1 and DNM3

Sézary syndrome is a unique cutaneous T-cell lymphoma as identified by an expanded gene signature including diagnostic marker molecules CDO1 and DNM3

The zinc finger transcription factor Th-POK regulates CD4 versus CD8 T-cell lineage commitment

Molecular Genetics of T Cell Development

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