The TNF receptor super family - NF-κB axis is critical to maintain effector regulatory T cells in lymphoid and non-lymphoid tissues
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ABSTRACT:
PROVIDER: PRJNA384469 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5483020.fastq.gz | Fastqsanger.gz | |||
| SRR5483030_1.fastq.gz | Fastqsanger.gz | |||
| SRR5483030_2.fastq.gz | Fastqsanger.gz | |||
| SRR5483021_1.fastq.gz | Fastqsanger.gz | |||
| SRR5483021_2.fastq.gz | Fastqsanger.gz |
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Project description:After exiting the thymus, Foxp3+ regulatory T (Treg) cells undergo further differentiation in the periphery resulting in the generation of effector (e)Treg cells, a process dependent on TCR signaling and the transcription factor IRF4. Here we show tumor necrosis factor receptor super family (TNFRSF) signaling plays a crucial role in the development and maintenance of eTreg cells. TNFRSF signaling activated the NF-κB transcription factor RelA and induced expansion and survival of eTreg cells in lymphoid and non-lymphoid tissues, including RORγt+ resident Treg cells in the small intestine. RelA regulated basic cellular processes in Treg cells, including cell survival and proliferation in response to TNFRSF signaling, but was not required for IRF4 expression or DNA binding, indicating that both pathways operate independently. Importantly, a similar pathway appeared to be active in humans, as patients with a point mutation in NF-κB1, a binding partner of RelA, had severely compromised Treg cells. Therefore, although TCR signaling is essential for eTreg cell differentiation, the TNFRSF-NF-κB axis was additionally required in a non-redundant manner to maintain the pool of eTreg cells.
2017-08-28 | GSE98263 | GEO
Project description:After exiting the thymus, Foxp3+ regulatory T (Treg) cells undergo further differentiation in the periphery resulting in the generation of effector (e)Treg cells, a process dependent on TCR signaling and the transcription factor IRF4. Here we show tumor necrosis factor receptor super family (TNFRSF) signaling plays a crucial role in the development and maintenance of eTreg cells. TNFRSF signaling activated the NF-κB transcription factor RelA and induced expansion and survival of eTreg cells in lymphoid and non-lymphoid tissues, including RORγt+ resident Treg cells in the small intestine. RelA regulated basic cellular processes in Treg cells, including cell survival and proliferation in response to TNFRSF signaling, but was not required for IRF4 expression or DNA binding, indicating that both pathways operate independently. Importantly, a similar pathway appeared to be active in humans, as patients with a point mutation in NF-κB1, a binding partner of RelA, had severely compromised Treg cells. Therefore, although TCR signaling is essential for eTreg cell differentiation, the TNFRSF-NF-κB axis was additionally required in a non-redundant manner to maintain the pool of eTreg cells.
2017-08-28 | GSE98262 | GEO
Project description:Pro-inflammatory cytokines were shown to promote growth and survival of cancerous cells. TNF induced RelA:p50 NF-κB dimer via the canonical pathway is thought to link inflammation with cancer. Integrating biochemical and computational studies we identify that deficiency of non-canonical signal transducer p100 triggers a positive autoregulatory loop, which instead perpetuates an alternate RelB:p50 containing NF-κB activity upon TNF treatment. TNF stimulated RelB:p50 dimer is sufficient for mediating NF-κB target gene-expressions and suppressing apoptotic cellular death independent of principal NF-κB subunit RelA. We further demonstrate that activating mutations in non-canonical NF-κB module deplete multiple myeloma cells of p100, thereby, provoking autoregulatory RelB:p50 activation. Finally, autoregulatory control reinforces protracted pro-survival NF-κB response, albeit comprising of RelB:p50, upon TNF priming that protects myeloma cells with dysfunctional p100 from subsequent apoptotic insults. In sum, we present evidence for positive autoregulation mediated through the NF-κB system and its potential involvement in human neoplasm.
2017-06-12 | GSE68615 | GEO
Project description:A20 is known key regulator of NF-κB activity and inflammatory response, but its role in the control of cell death receptor signaling is not completely understood. Although A20 is widely accepted anti-apoptotic protein, we demonstrate that elevated expression of A20 in both, human and murine keratinocytes results in sensitisation to TNF-induced cell death. We prove that the Ripoptosome formation in A20 overexpressing cells is prerequisite for the TNF-induced cell death execution. We demonstrate that both canonical and non-canonical NF-κB signaling pathways are regulated upon increase of A20 expression. A20 dependent alteration of cIAPs and TRAF1 expressions are involved in the multiple level control of cell death in keratinocytes with elevated A20 expression.
2020-02-20 | GSE128248 | GEO
Project description:A20 is known key regulator of NF-κB activity and inflammatory response, but its role in the control of cell death receptor signaling is not completely understood. Although A20 is widely accepted anti-apoptotic protein, we demonstrate that elevated expression of A20 in both, human and murine keratinocytes results in sensitisation to TNF-induced cell death. We prove that the Ripoptosome formation in A20 overexpressing cells is prerequisite for the TNF-induced cell death execution. We demonstrate that both canonical and non-canonical NF-κB signaling pathways are regulated upon increase of A20 expression. A20 dependent alteration of cIAPs and TRAF1 expressions are involved in the multiple level control of cell death in keratinocytes with elevated A20 expression.
2020-02-20 | GSE128247 | GEO
Project description:Background: Cancer immunotherapeutic strategies showed unprecedented results in the clinic. However, many patients do not respond to immuno-oncological treatments due to the occurrence of a plethora of immunological obstacles, including tumor intrinsic mechanisms of resistance to cytotoxic T cell attack. Thus, a deeper understanding of these mechanisms is needed to develop successful immunotherapies. Methods: To identify novel genes that protect tumor cells from effective T cell-mediated cytotoxicity, we performed a genetic screening in pancreatic cancer cells challenged with TILs and antigen-specific T cells. Results: The screening revealed 108 potential genes that protected tumor cells from T cell attack. Among them, salt-inducible kinase 3 (SIK3) was one of the strongest hits identified in the screening. Both genetic and pharmacological inhibition of SIK3 in tumor cells dramatically increased T cell-mediated cytotoxicity in several in vitro co-culture models, using different sources of tumor and T cells. Consistently, adoptive T cell transfer of TILs led to tumor growth inhibition of SIK3 depleted cancer cells in vivo. Mechanistic analysis revealed that SIK3 rendered tumor cells susceptible to TNF secreted by tumor-activated T cells. SIK3 promoted NF-ΚB nuclear translocation and inhibited Caspase-8 and -9 after TNF stimulation. Chromatin accessibility and transcriptome analyses showed that SIK3 knockdown profoundly impaired the expression of pro-survival genes under the TNF-NF-ΚB axis. TNF stimulation led to SIK3-dependent phosphorylation of the NF-κB upstream regulators inhibitory-κB kinase (IKK) and NF-kappa-B inhibitor alpha (IκBα) on the one side, and to inhibition of histone deacetylase 4 (HDAC4) on the other side, thus sustaining NF-κB activation and nuclear stabilization. A SIK3 dependent gene signature of TNF-mediated NF-κB activation was found in a majority of pancreatic cancers where it correlated with increased cytotoxic T cell activity and poor prognosis.
2022-06-06 | GSE202304 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-08-28 | GSE98264 | GEO
Project description:Mouse aorta smooth muscle cells (SMCs) express TNF receptor superfamily member 1A (TNFR1) and lymphotoxin ß receptor (LTßR). Circumstantial evidence has linked the SMC LTßR to tertiary lymphoid organogenesis in diseased aortae of hyperlipidemic mice. Here, we explored potential roles of TNFR1 and LTßR activation in cultured SMCs. TNFR1 signaling by TNF activated the classical RelA NF-κB pathway, whereas LTßR signaling by agonistic anti LTßR antibody activated both the classical RelA and alternative RelB NF-κB pathways. Addition of both agonists synergized to enhance p100 inhibitor processing to the p52 subunit of NF-κB and promoted its nuclear translocation suggesting RelA-RelB cross-talk in transcription regulation. Correspondingly, microarrays showed that simultaneous TNFR1 and LTßR activation when compared to activation of single receptors was followed by markedly elevated levels of mRNAs encoding leukocyte homeostatic chemokines CCL2, CCL5, CXCL1, and CX3CL1. Furthermore, SMCs acquired prototypical features of mesenchymal cells known as lymphoid tissue organizers (LTOs), which control tertiary lymphoid organogenesis in autoimmune diseases, through hyperinduction of CCL7, CCL9, CXCL13, CCL19, CXCL16, VCAM-1, and ICAM-1. Experiments with ltbr-/- SMCs suggested that the LTßR-RelB activation component of NF-κB signaling was obligatory to generate the LTO phenotype. TNFR1-LTßR crosstalk also resulted in augmented synthesis and prolonged secretion of lymphorganogenic chemokine proteins into the culture medium. Thus, combined TNFR1-LTßR signaling triggers SMC transdifferentiation into a phenotype that strikingly resembles LTOs. LTO-like SMCs may adopt a thus far unrecognized role in diseased arteries, i.e. to coordinate tertiary lymphoid organogenesis in atherosclerosis, aortic aneurysm, and transplant vasculopathy.
2009-11-23 | GSE15062 | GEO
Project description:MTD project_description Inflammation and decreased stem cell function characterize organism aging, yet the relationship between these factors remains incompletely understood. This study shows that aged hematopoietic stem and progenitor cells exhibit increased ground-stage NF-κB activity, which enhances their responsiveness to undergo differentiation and loss of self-renewal in response to inflammation. The study identifies Rad21/cohesin as a critical mediator of NF-κB signals, by increasing chromatin accessibility of inter-/intra-genic and enhancer regions. Rad21/NF-κB are required for normal differentiation, but limit self-renewal of hematopoietic stem cells (HSCs) during aging and inflammation in an NF-κB dependent manner. HSCs from aged mice fail to downregulate Rad21/cohesin and inflammation/differentiation inducing signals in the resolution phase after acute inflammation. and The inhibition of cohesin/NF-κB is sufficient to revert the hypersensitivity of aged HSPCs to inflammation-induced differentiation. During aging, myeloid-biased HSCs with disrupted and naturally occurring reduced expression of Rad21/cohesin are increasingly selected over lymphoid-biased HSCs. Together, Rad21/cohesin mediated NF-κB signaling limits HSPC function during aging and selects for cohesin deficient HSCs with myeloid skewed differentiation.
2018-11-28 | PXD011537 | Pride
Project description:A20 contribution to NF-κB regulation, Ripoptosome formation and TNF-induced cell death
| PRJNA526879 | ENA