The zinc finger protein cKrox directs CD4 lineage differentiation during intrathymic T cell positive selection

Sun, Guangping; Liu, Xiaolong; Mercado, Peter; Jenkinson, S. Rhiannon; Kypriotou, Magdalini; Feigenbaum, Lionel; Galéra, Philippe; Bosselut, Rémy

doi:10.1038/ni1183

Cited by 241 publications

(317 citation statements)

References 50 publications

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“…Moreover, mutation of Th-POK leads to the redirection of MHC-II-selected thymocytes to the CD8 lineage (1)(2)(3)(4). Other transcription factors have also been implicated in CD4/CD8-lineage commitment, including GATA-3, which is required for CD4-lineage development (5-7), TOX that can direct CD8-lineage development (8), and Runx3, which is involved in silencing CD4 gene expression in CD8-lineage cells (9,10).…”

Section: Compared With Mhc Class I (Mhc-i)mentioning

confidence: 99%

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CCR7 Expression in Developing Thymocytes Is Linked to the CD4 versus CD8 Lineage Decision

Yin

Ladi

Chan

et al. 2007

The Journal of Immunology

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During thymic development, T cell progenitors undergo positive selection based on the ability of their T cell Ag receptors (TCR) to bind MHC ligands on thymic epithelial cells. Positive selection determines T cell fate, in that thymocytes whose TCR bind MHC class I (MHC-I) develop as CD8-lineage T cells, whereas those that bind MHC class II (MHC-II) develop as CD4 T cells. Positive selection also induces migration from the cortex to the medulla driven by the chemokine receptor CCR7. In this study, we show that CCR7 is up-regulated in a larger proportion of CD4+CD8+ thymocytes undergoing positive selection on MHC-I compared with MHC-II. Mice bearing a mutation of Th-POK, a key CD4/CD8-lineage regulator, display increased expression of CCR7 among MHC-II-specific CD4+CD8+ thymocytes. In addition, overexpression of CCR7 results in increased development of CD8 T cells bearing MHC-II-specific TCR. These findings suggest that the timing of CCR7 expression relative to coreceptor down-regulation is regulated by lineage commitment signals.

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Section: Compared With Mhc Class I (Mhc-i)mentioning

confidence: 99%

“…In particular, the zinc finger transcription factor Th-POK appears to act as a master regulator of lineage commitment (1,2). Th-POK is preferentially expressed in thymocytes during positive selection by MHC class II (MHC-II) 3 …”

mentioning

confidence: 99%

CCR7 Expression in Developing Thymocytes Is Linked to the CD4 versus CD8 Lineage Decision

Yin

Ladi

Chan

et al. 2007

The Journal of Immunology

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“…Promyelocyticzinc finger transcription regulator may control the development of iNKT cells, as mice lacking it exhibit an ,90% decrease in the number of thymic iNKT cells, and the iNKT cells presents how a defect in secretion of Th1 and Th2 cytokines upon stimulation. 20,21 Studies have demonstrated that the zincfinger transcription factor, ThPok (also called ZBTB7B or cKrox), drives CD4 expression on MHC class II-restricted T cells 22,23 by inhibiting the Runx1-and Runx3-mediated downregulation of CD4 in ab T cells. 24 Interestingly, subsequent research revealed that ThPok-deficient iNKT cells were unable to express CD4, and a subset of CD8 1 NKT cells was instead detected.…”

Section: Introductionmentioning

confidence: 99%

Runt-related transcription factor 3 is involved in the altered phenotype and function in ThPok-deficient invariant natural killer T cells

et al. 2014

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The interplay between the CD4-lineage transcription factor ThPok and the CD8-lineage transcription factor, runt-related transcription factor 3 (Runx3), in T-cell development has been extensively documented. However, little is known about the roles of these transcription factors in invariant natural killer T (iNKT) cell development. CD1d-restricted iNKT cells are committed to the CD4 1 CD8 2 and CD4 2 CD8 2 sublineages, which respond to antigen stimulation with rapid and potent release of T helper (Th) 1 and Th2 cytokines. However, previous reports have demonstrated a new population of CD8 1 NKT cells in ThPok-deficient mice. In the current study, we sought to determine whether Runx3 was involved in the re-expression of CD8 and function of iNKT cells in the absence of ThPok. We used mice lacking Runx3, ThPok or both and verified that Runx3 was partially responsible for the appearance of CD8 1 iNKT cells in ThPok knockout mice. Additionally, Runx3 participated in the immune response mediated by iNKT cells in a model of a-galactosylceramide-induced acute hepatitis. These results indicate that Runx3 is crucial for the phenotypic and functional changes observed in ThPok-deficient iNKT cells. and the canonical T-cell receptor a (TCRa) chain (Va14-Ja18 in mice and V24-J18 in humans) coupled to specific Vb chains (Vb8, Vb7 and Vb2 in mice and Vb11 in humans). These receptors are responsible for the interaction of NKT cells with CD1d molecules expressed on CD4 1 CD8 1 double-positive (DP) thymocytes. 1 NKT cells are classified into type I (defined as invariant (iNKT) or classical NKT cells) and type II based on the antigens recognized by each and their TCR repertoires. 2 Our study focused on type I NKT cells (hereafter referred to as iNKT cells). iNKT cells recognize the glycosphingolipid antigen a-galactosylceramide (a-GalCer) and a-GalCer loading with the tetrameric form of CD1d is often used to define the iNKT cell subset because of the high affinity of CD1d for the iNKT cell TCR. 3 Although iNKT cells originate from CD4 1 CD8 1 (DP) thymocytes 4 and are selected by MHC class

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“…Transcription factor ThPOK encoded by the Zbtb7b gene (hereafter referred to as the Thpok gene) is essential for development of CD4 + Th cells. Previous genetic studies have shown that the presence or absence of ThPOK in postselection thymocytes is a crucial factor that discriminates CD4/CD8 lineages (2,3). Therefore, elucidation of mechanisms that control Thpok expression has been a major subject to understand how cell fate determination is regulated at the transcriptional level.…”

mentioning

confidence: 99%

Cutting Edge: Fine-Tuning of Thpok Gene Activation by an Enhancer in Close Proximity to Its Own Silencer

Muroi

Tanaka

Miyamoto

et al. 2013

The Journal of Immunology

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Differentiation of MHC class II–selected thymocytes toward the CD4+ helper lineage depends on function of the transcription factor ThPOK, whose expression is repressed in CD8+ cytotoxic lineage cells by a transcriptional silencer activity within the distal regulatory element (DRE) in the Thpok gene. Interestingly, the DRE also functions as a transcriptional enhancer. However, how the DRE exerts such dual functionality remains obscure. In this study, we dissected the DRE and identified DNA sequences specifically responsible for enhancer activity, and designated this as the thymic enhancer. Removal of the thymic enhancer from the murine Thpok locus resulted in inefficient ThPOK induction, thereby inducing a redirection toward alternative CD8+ cytotoxic lineage in a proportion of MHC class II–selected cells, even when they express monoclonal MHC class II–restricted transgenic TCR. Thus, regulation of contiguous but separable sequences with opposite function in the DRE plays an important role in precise coupling of TCR signaling with the selection process of two opposite lineages.

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The zinc finger protein cKrox directs CD4 lineage differentiation during intrathymic T cell positive selection

Cited by 241 publications

References 50 publications

CCR7 Expression in Developing Thymocytes Is Linked to the CD4 versus CD8 Lineage Decision

CCR7 Expression in Developing Thymocytes Is Linked to the CD4 versus CD8 Lineage Decision

Runt-related transcription factor 3 is involved in the altered phenotype and function in ThPok-deficient invariant natural killer T cells

Cutting Edge: Fine-Tuning of Thpok Gene Activation by an Enhancer in Close Proximity to Its Own Silencer

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