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The transcription factor PLZF directs the effector program of the NKT cell lineage.

ABSTRACT: The transcriptional control of CD1d-restricted NKT cell development has remained elusive. We report that PLZF (promyelocytic leukemia zinc finger, Zbtb16), a member of the BTB/POZ-ZF family of transcription factors that includes the CD4-lineage-specific c-Krox (Th-POK), is exquisitely specific to CD1d-restricted NKT cells and human MR1-specific MAIT cells. PLZF was induced immediately after positive selection of NKT cell precursors, and PLZF-deficient NKT cells failed to undergo the intrathymic expansion and effector differentiation that characterize their lineage. Instead, they preserved a naive phenotype and were directed to lymph nodes. Conversely, transgenic expression of PLZF induced CD4(+) thymocytes to acquire effector differentiation and migrate to nonlymphoid tissues. We suggest that PLZF is a transcriptional signature of NKT cells that directs their innate-like effector differentiation during thymic development.

SUBMITTER: Savage AK

PROVIDER: S-EPMC2613001 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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The transcription factor PLZF directs the effector program of the NKT cell lineage.

Savage Adam K AK Constantinides Michael G MG Han Jin J Picard Damien D Martin Emmanuel E Li Bofeng B Lantz Olivier O Bendelac Albert A

Immunity 20080814 3

The transcriptional control of CD1d-restricted NKT cell development has remained elusive. We report that PLZF (promyelocytic leukemia zinc finger, Zbtb16), a member of the BTB/POZ-ZF family of transcription factors that includes the CD4-lineage-specific c-Krox (Th-POK), is exquisitely specific to CD1d-restricted NKT cells and human MR1-specific MAIT cells. PLZF was induced immediately after positive selection of NKT cell precursors, and PLZF-deficient NKT cells failed to undergo the intrathymic ...[more]

PMID: 18703361

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Let-7 microRNAs target the lineage-specific transcription factor PLZF to regulate terminal NKT cell differentiation and effector function.

Project description:Lethal-7 (let-7) microRNAs (miRNAs) are the most abundant miRNAs in the genome, but their role in developing thymocytes is unclear. We found that let-7 miRNAs targeted Zbtb16 mRNA, which encodes the lineage-specific transcription factor PLZF, to post-transcriptionally regulate PLZF expression and thereby the effector functions of natural killer T cells (NKT cells). Dynamic upregulation of let-7 miRNAs during the development of NKT thymocytes downregulated PLZF expression and directed their terminal differentiation into interferon-γ (IFN-γ)-producing NKT1 cells. Without upregulation of let-7 miRNAs, NKT thymocytes maintained high PLZF expression and terminally differentiated into interleukin 4 (IL-4)-producing NKT2 cells or IL-17-producing NKT17 cells. Upregulation of let-7 miRNAs in developing NKT thymocytes was signaled by IL-15, vitamin D and retinoic acid. Such targeting of a lineage-specific transcription factor by miRNA represents a previously unknown level of developmental regulation in the thymus.

| S-EPMC4406853 | biostudies-literature

Multiple layers of transcriptional regulation by PLZF in NKT-cell development.

Project description:The transcription factor PLZF [promyelocytic leukemia zinc finger, encoded by zinc finger BTB domain containing 16 (Zbtb16)] is induced during the development of innate and innate-like lymphocytes to direct their acquisition of a T-helper effector program, but the molecular mechanisms involved are poorly understood. Using biotinylation-based ChIP-seq and microarray analysis of both natural killer T (NKT) cells and PLZF-transgenic thymocytes, we identified several layers of regulation of the innate-like NKT effector program. First, PLZF bound and regulated genes encoding cytokine receptors as well as homing and adhesion receptors; second, PLZF bound and activated T-helper-specific transcription factor genes that in turn control T-helper-specific programs; finally, PLZF bound and suppressed the transcription of Bach2, a potent general repressor of effector differentiation in naive T cells. These findings reveal the multilayered architecture of the transcriptional program recruited by PLZF and elucidate how a single transcription factor can drive the developmental acquisition of a broad effector program.

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PLZF acetylation levels regulate NKT cell differentiation

Project description:The transcription factor PLZF (promyelocytic leukemia zinc finger) is encoded by the BTB 42 domain-containing 16 (Zbtb16) gene. Its repressor function regulates specific transcriptional 43 programs. During the development of invariant natural killer T (NKT) cells, PLZF is 44 expressed and directs their effector program but the detailed mechanisms underlying PLZF 45 regulation of multi-stage NKT cell developmental program are not well understood. This 46 study investigated the role of acetylation-induced PLZF activation on NKT cell development 47 by analyzing mice expressing a mutant form of PLZF mimicking constitutive acetylation (PLZFON mice). NKT populations in PLZFON 48 mice were reduced in proportion and numbers 49 of cells, and the cells present were blocked at the transition from developmental stage 1 to stage 2. NKT cell subset differentiation was also altered, with T-bet+ NKT1 and RORJt + 50 NKT17 subsets dramatically reduced, and the emergence of a T-bet - RORJt - 51 NKT cell subset 52 with features of cells in early developmental stages rather than mature NKT2 cells. Analysis 53 of DNA methylation patterns indicated that activated PLZF establishes a unique DNA 54 methylation signature to regulate NKT cells’ entry into the early stages of development, while 55 repressing maturation. In wild-type NKT cells, deacetylation of PLZF alleviates this 56 repression and allows subsequent NKT cell differentiation. Interestingly, development of 57 other innate lymphoid and myeloid cells, that are dependent on PLZF for their generation, is not altered in PLZFON 58 mice highlighting lineage specific regulation. Overall, we propose that 59 specific epigenetic control of PLZF through acetylation levels is required to regulate normal 60 NKT cell differentiation.

2021-04-21 | GSE171984 | GEO

PLZF acetylation levels regulate NKT cell diffrentiation

Project description:The transcription factor PLZF (promyelocytic leukemia zinc finger) is encoded by the BTB domain-containing 16 (Zbtb16) gene. Its repressor function regulates specific transcriptional programs. During the development of invariant natural killer T (NKT) cells, PLZF is expressed and directs their effector program but the detailed mechanisms underlying PLZF regulation of multi-stage NKT cell developmental program are not well understood. This study investigated the role of acetylation-induced PLZF activation on NKT cell development by analyzing mice expressing a mutant form of PLZF mimicking constitutive acetylation (PLZFON mice). NKT populations in PLZFON mice were reduced in proportion and numbers of cells, and the cells present were blocked at the transition from developmental stage 1 to stage 2. NKT cell subset differentiation was also altered, with T-bet+ NKT1 and RORt+ NKT17 subsets dramatically reduced, and the emergence of a T-bet-RORt- NKT cell subset with features of cells in early developmental stages rather than mature NKT2 cells. Preliminary analysis of DNA methylation patterns suggested that activated PLZF acts on the DNA methylation signature to regulate NKT cells’ entry into the early stages of development, while repressing maturation. In wild-type NKT cells, deacetylation of PLZF is possible, allowing subsequent NKT cell differentiation. Interestingly, development of other innate lymphoid and myeloid cells, that are dependent on PLZF for their generation, is not altered in PLZFON mice highlighting lineage specific regulation. Overall, we propose that specific epigenetic control of PLZF through acetylation levels is required to regulate normal NKT cell differentiation. Key points: Constitutive acetylation of PLZF (PLZFON) blocks NKT cell development. PLZFON might act on the DNA methylation signature to control gene expression. PLZF acetylation levels regulate normal NKT cell differentiation.

2021-05-24 | GSE128558 | GEO

Inflammation directs memory precursor and short-lived effector CD8(+) T cell fates via the graded expression of T-bet transcription factor.

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An NF-κB Transcription-Factor-Dependent Lineage-Specific Transcriptional Program Promotes Regulatory T Cell Identity and Function.

Project description:Both conventional T (Tconv) cells and regulatory T (Treg) cells are activated through ligation of the T cell receptor (TCR) complex, leading to the induction of the transcription factor NF-κB. In Tconv cells, NF-κB regulates expression of genes essential for T cell activation, proliferation, and function. However the role of NF-κB in Treg function remains unclear. We conditionally deleted canonical NF-κB members p65 and c-Rel in developing and mature Treg cells and found they have unique but partially redundant roles. c-Rel was critical for thymic Treg development while p65 was essential for mature Treg identity and maintenance of immune tolerance. Transcriptome and NF-κB p65 binding analyses demonstrated a lineage specific, NF-κB-dependent transcriptional program, enabled by enhanced chromatin accessibility. These dual roles of canonical NF-κB in Tconv and Treg cells highlight the functional plasticity of the NF-κB signaling pathway and underscores the need for more selective strategies to therapeutically target NF-κB.

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Expression data comparing PLZF+/+, PLZF +/lu, PLZF lu/lu gammadelta NKT cells

2012-11-09 | E-GEOD-42168 | biostudies-arrayexpress

Expression data comparing PLZF+/+, PLZF +/lu, PLZF lu/lu gammadelta NKT cells

2012-11-09 | GSE42168 | GEO

Transcription factor IRF8 directs a silencing programme for TH17 cell differentiation.

Project description:T(H)17 cells are recognized as a unique subset of T helper cells that have critical roles in the pathogenesis of autoimmunity and tissue inflammation. Although RORγt is necessary for the generation of T(H)17 cells, the molecular mechanisms underlying the functional diversity of T(H)17 cells are not fully understood. Here we show that a member of interferon regulatory factor (IRF) family of transcription factors, IRF8, has a critical role in silencing T(H)17-cell differentiation. Mice with a conventional knockout, as well as a T cell-specific deletion, of the Irf8 gene exhibited more efficient T(H)17 cells. Indeed, studies of an experimental model of colitis showed that IRF8 deficiency resulted in more severe inflammation with an enhanced T(H)17 phenotype. IRF8 was induced steadily and inhibited T(H)17-cell differentiation during T(H)17 lineage commitment at least in part through its physical interaction with RORγt. These findings define IRF8 as a novel intrinsic transcriptional inhibitor of T(H)17-cell differentiation.

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PLZF Controls the Expression of a Limited Number of Genes Essential for NKT Cell Function.

Project description:Natural killer (NKT) T cells exhibit tissue distribution, surface phenotype, and functional responses that are strikingly different from those of conventional T cells. The transcription factor PLZF is responsible for most of these properties, as its ectopic expression in conventional T cells is sufficient to confer to them an NKT-like phenotype. The molecular program downstream of PLZF, however, is largely unexplored. Here we report that PLZF regulates the expression of a surprisingly small set of genes, many with known immune functions. This includes several established components of the NKT cell developmental program. Expression of the transcriptional regulators Id2, previously shown to be required for iNKT cell survival in the liver and c-Maf, which shapes the NKT cytokine profile, was compromised in PLZF-deficient cells. Ectopic expression of c-Maf complemented the cells' defect in producing IL-4 and IL-10. PLZF also induced a program of cell surface receptors which shape the NKT cell's response to external stimuli, including the costimulatory receptor ICOS and the cytokine receptors IL12rb1 and IL18r1. As an ensemble, the known functions of the molecules whose expression is affected by PLZF explain many defects observed in PLZF(-/-) NKT cells.

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