TNF activation of NF-κB is essential for development of single-positive thymocytes

Webb, Louise V.; Ley, Steven C.; Seddon, Benedict

doi:10.1084/jem.20151604

Cited by 37 publications

(89 citation statements)

References 34 publications

(44 reference statements)

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“…Several lines of evidence suggest that induction of these cell death pathways does not account for the T-cell developmental defects we observed: (1) simultaneous genetic ablation of both of these cell death pathways did not rescue the impaired generation of thymic Treg cells in Sharpin cpdm mice or the block in conventional thymocyte differentiation in Hoip ΔCd4 mice; (2) HOIL-1-, HOIP- and SHARPIN-deficient thymocytes were not predisposed to TNF-induced cell death; (3) pharmacologic inhibition of apoptosis or necroptosis did not alter thymocyte viability; and (4) TNF blockade in vivo did not rescue thymocyte differentiation in Hoip ΔCd4 mice or the loss of Treg cells in Hoip ΔFoxp3 mice. These data contrast recent findings that TNF deficiency could restore late thymocyte differentiation in IKK-deficient mice51 or TAK1-deficient mice5 and suggest roles for LUBAC beyond inhibiting TNF-induced cell death. In addition, the failure of combined BAX/BAK deletion to rescue SP thymocyte maturation in Hoip ΔCd4 mice provides evidence that LUBAC activity is not required to antagonize thymocyte deletion triggered by BH3-only proteins or to mediate cytokine-derived survival programmes (such as IL-7 or IL-2), stimuli that affect the mitochondrial pathway of apoptosis.…”

Section: Discussioncontrasting

confidence: 99%

Linear ubiquitin chain assembly complex coordinates late thymic T-cell differentiation and regulatory T-cell homeostasis

et al. 2016

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The linear ubiquitin chain assembly complex (LUBAC) is essential for innate immunity in mice and humans, yet its role in adaptive immunity is unclear. Here we show that the LUBAC components HOIP, HOIL-1 and SHARPIN have essential roles in late thymocyte differentiation, FOXP3+ regulatory T (Treg)-cell development and Treg cell homeostasis. LUBAC activity is not required to prevent TNF-induced apoptosis or necroptosis but is necessary for the transcriptional programme of the penultimate stage of thymocyte differentiation. Treg cell-specific ablation of HOIP causes severe Treg cell deficiency and lethal immune pathology, revealing an ongoing requirement of LUBAC activity for Treg cell homeostasis. These data reveal stage-specific requirements for LUBAC in coordinating the signals required for T-cell differentiation.

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Section: Discussioncontrasting

confidence: 99%

Linear ubiquitin chain assembly complex coordinates late thymic T-cell differentiation and regulatory T-cell homeostasis

et al. 2016

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“…Tumor necrosis factor (TNF) acts on a wide range of cell types and is a critical mediator of inflammatory and stress responses (1) and of the development of certain immune cells, including T lymphocytes (2,3). TNF stimulation activates a signaling cascade that disrupts the interaction between the transcription factor nuclear factor-kB (NF-kB) and the inhibitor of NF-kB a (IkBa), thereby releasing NF-kB and allowing it to accumulate in the nucleus.…”

Section: Introductionmentioning

confidence: 99%

Fold-Change Detection of NF-κB at Target Genes with Different Transcript Outputs

Wong

Mathew

Ramji

et al. 2019

Biophysical Journal

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The transcription factor nuclear factor (NF)-kB promotes inflammatory and stress-responsive gene transcription across a range of cell types in response to the cytokine tumor necrosis factor (TNF). Although NF-kB signaling exhibits significant variability across single cells, some target genes supporting high levels of TNF-inducible transcription exhibit fold-change detection of NF-kB, which may buffer against stochastic variation in signaling molecules. It is unknown whether fold-change detection is maintained at NF-kB target genes with low levels of TNF-inducible transcription, for which stochastic promoter events may be more pronounced. Here, we used a microfluidic cell-trapping device to measure how TNF-induced activation of NF-kB controls transcription in single Jurkat T cells at the promoters of integrated HIV and the endogenous cytokine gene IL6, which produce only a few transcripts per cell. We tracked TNF-stimulated NF-kB RelA nuclear translocation by live-cell imaging and then quantified transcript number by RNA FISH in the same cell. We found that TNF-induced transcript abundance at 2 h for low-and high-abundance target genes correlates with similar strength with the fold change in nuclear NF-kB. A computational model of TNF-NF-kB signaling, which implements fold-change detection from competition for binding to kB motifs, could reproduce fold-change detection across the experimentally measured range of transcript outputs. However, multiple model parameters affecting transcription had to be simultaneously varied across promoters to maintain fold-change detection while also matching other trends in the single-cell data for low-abundance transcripts. Our results suggest that cells use multiple biological mechanisms to tune transcriptional output while maintaining robustness of NF-kB fold-change detection.

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“…Tumor necrosis factor alpha (TNF) acts on a wide range of cell types and is a critical mediator of inflammatory and stress responses (1) and of the development of certain immune cells, including T lymphocytes (2,3). TNF stimulation activates a signaling cascade that disrupts the interaction between the transcription factor nuclear factor-κB (NF-κB) and the inhibitor of nuclear factor-B alpha (IB), thereby releasing NF-κB and allowing it to accumulate in the nucleus.…”

Section: Introductionmentioning

confidence: 99%

Fold-change detection of NF-κB at target genes with different transcript outputs

Wong¹,

Ramji²,

Gaudet³

et al. 2018

Preprint

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The transcription factor NF-B promotes inflammatory and stress-responsive gene transcription across a range of cell types in response to the cytokine tumor necrosis factor- (TNF). Although NF-B signaling exhibits significant variability across single cells, some target genes exhibit fold-change detection of NF-B, which may buffer against stochastic variation in signaling molecules. However, this observation was made at target genes supporting high levels of TNF-inducible transcription. It is unknown if fold-change detection is maintained at NF-B target genes with low levels of TNF-inducible transcription, for which stochastic promoter events may be more pronounced. Here we used a microfluidic cell-trapping device to measure how TNF-induced activation of NF-κB controls transcription in single Jurkat T cells at the promoters of integrated HIV and the endogenous cytokine gene IL6, which produce only a few transcripts per cell. We tracked TNF-stimulated NF-κB RelA nuclear translocation by live-cell imaging and then quantified transcript number by RNA FISH in the same cell. We found that TNF-induced transcription correlates with fold change in nuclear NF-κB with similar strength at low versus high abundance target genes. A computational model of TNF-NF-κB signaling, which implements fold-change detection from competition for binding to κB motifs, was sufficient to reproduce fold-change detection across the experimentally measured range of transcript outputs. Nevertheless, we found that gene-specific trends in transcriptional noise and levels of promoter-bound NF-κB predicted by the model were inconsistent with our experimental observations at low abundance gene targets. Our results reveal a gap in our understanding of RelA-mediated transcription for low abundance transcripts and suggest that cells use additional biological mechanisms to maintain robustness of NF-κB foldchange detection while tuning transcriptional output.

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TNF activation of NF-κB is essential for development of single-positive thymocytes

Abstract: Seddon and colleagues study mice whose T cells lack both of the catalytic subunits of the IKK complex and show that impaired TNF receptor activation of NF-κB is responsible for their block in thymocyte development.

Cited by 37 publications

References 34 publications

Linear ubiquitin chain assembly complex coordinates late thymic T-cell differentiation and regulatory T-cell homeostasis

Linear ubiquitin chain assembly complex coordinates late thymic T-cell differentiation and regulatory T-cell homeostasis

Fold-Change Detection of NF-κB at Target Genes with Different Transcript Outputs

Fold-change detection of NF-κB at target genes with different transcript outputs

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