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TLR9 deficiency promotes CD73 expression in T cells and diabetes protection in NOD mice

ABSTRACT: Analyze the effect of TLR9 deficiency on immue cell function at the gene expression level. Our hypothesis was that TLR9 deficiency promotes CD73 expression in T cells thus regulates autoimmune diabetes development in NOD mice. Sorted TCRb+ cells were pooled from several mice for furhter RNA extraction and cRNA labeling.

ORGANISM(S): Mus musculus

SUBMITTER: NINGWEN TAI

PROVIDER: E-GEOD-48781 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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TLR9 deficiency promotes CD73 expression in T cells and diabetes protection in NOD mice

Project description:Analyze the effect of TLR9 deficiency on immue cell function at the gene expression level. Our hypothesis was that TLR9 deficiency promotes CD73 expression in T cells thus regulates autoimmune diabetes development in NOD mice.

2013-07-11 | GSE48781 | GEO

Cell intrinsic expression of TLR9 in autoreactive B cells constrains BCR/TLR7-dependent responses

Project description:Endosomal Toll-like receptors (TLRs) play an important role in the etiology of systemic autoimmune diseases such as SLE, where DNA- and RNA-associated autoantigens activate autoreactive B cells through TLR9- and TLR7-dependent pathways, respectively. Nevertheless, TLR9-deficient autoimmune prone mice develop more severe clinical disease, while TLR7-deficient and TLR7/9-double deficient autoimmune-prone mice develop less severe disease. To determine whether the regulatory activity of TLR9 is B cell intrinsic, we have now directly compared the functional properties of autoantigen activated WT, TLR9-deficient and TLR7-deficient B cells, in an experimental system where proliferation depends on BCR/TLR co-engagement. In vitro, TLR9-deficient cells are less dependent on survival factors for a sustained proliferative response than either WT or TLR7-deficient cells. The TLR9-deficient cells also preferentially differentiate toward the plasma cell lineage, as indicated by expression of CD138, sustained expression of IRF4, and other molecular markers of plasma cells. In vivo, autoantigen-activated TLR9-deficient cells give rise to greater numbers of autoantibody producing cells. Our results identify distinct roles for TLR7 and TLR9 in the differentiation of autoreactive B cells that explain the capacity of TLR9 to limit, and TLR7 to promote, the clinical features of SLE. AM14 WT, Tlr7-/-, Tlr9-/- and Tlr7/9-/- B cells were stimulated with PL2-3 for 0, 6, 24, and 42 hours, for a total of 16 samples.

2015-03-04 | E-GEOD-58756 | biostudies-arrayexpress

Transcription profiling by sequencing of murine MyD88 -/- and MyD88 +/+ mTECs stimulated with a TLR9 ligand

Project description:We compared in vitro mTECs-high stimulated with TLR9 ligand CpG ODN (1826) or non stimulated from MyD88 -/- and MyD88 +/+ mice: Thymi were enzymaticaly digested, cells were MACS enriched for CD45- fraction, and FACS sorted using BD Influx sorter. mTECs-high were gated as EpCAM+CD11c-Ly51-MHCII+CD80+. Cell from MyD88 -/- and MyD88 +/+ mice were incubated in RPMI with or without CpG ODN (1826) for 24 hours. Total RNA was isolated using RNeasy Plus Micro Kit (Qiagen). 4 samples per condition were used.

2020-03-20 | E-MTAB-8025 | biostudies-arrayexpress

ATAC-seq analysis of aged-associated B cells (ABC) across three TLR9 genotypes (TLR9WT, TLR9-/- and non-signaling TLR9P915H/P915H) isolated from a mixed chimeric setting in the MRL/lpr murine model of systemic lupus erythematosus.

Project description:Purpose: The goal of this study was to assess if TLR9 deficiency (TLR9-/-) or TLR9 incapacity to signal through MyD88 would differentially influence the epigenetic states of ABC, in a B cell intrinsic manner. Methods : Mixed bone marrow chimeras of one-third each TLR9+/+ CD45.1/2, TLR9-/- CD45.1/1 and TLR9P915H/P915H CD45.2/2 were generated on the MRL/lpr background. From each recipient, ABC were sorted with respect to the CD45 congenic markers at [20 weeks] post chimerism. DNA was isolated using a protocol adapted from Corces et al. Samples were sequenced to obtain 20M 2x75 bp paired-end reads using an Illumina NextSeq 550 sequencer (Illumina, Inc, California, USA). Results: The majority of differences in open chromatin regions were observed between TLR9-/- and TLR9P915H ABCs. This must reflect the MyD88-independent regulatory function of TLR9 (lost in TLR9-/- and present in TLR9P915H).

2022-08-03 | GSE202103 | GEO

IRF-5 and IRF-8 govern the response of Human Plasmacytoid Dendritic Cells following TLR9 ligation

Project description:Synthetic oligonucleotides (ODNs) containing CpG motifs stimulate human plasmacytoid dendritic cells (pDCs) to produce type-1 interferons (IFN) and pro-inflammatory cytokines. Previous studies demonstrated that interferon regulatory factors (IRFs) played a central role in mediating CpG-induced pDC activation. This work explores the inverse effects of IRF-5 and IRF-8 on CpG dependent gene expression. Results from RNA interference and microarray studies indicate that IRF-5 up-regulates TLR9-driven gene expression whereas IRF-8 down-regulates the same genes. Several findings support the conclusion that IRF-8 inhibits TLR9 dependent gene expression by directly blocking the activity of IRF-5. First, the inhibitory activity of IRF-8 is only observed when IRF-5 is present. Second, proximity ligation analysis shows that IRF-8 and IRF-5 co-localize within the cytoplasm of resting human pDC and co-translocate to the nucleus after CpG stimulation. Taken together, these findings suggest that two transcription factors with opposing functions control TLR9 signaling in human pDCs. CAL-1 cells were transfected with siRNA targeting IRF-5 (IRF-5si) and left unstimulated (n=4, technical repeats) or stimulated with K-type CpG ODN (n=4, technical repeats). CAL-1 cells were transfected with siRNA targeting IRF-8 (IRF-8si) and left unstimulated (n=4, technical repeats) or stimulated with K-type CpG ODN (n=4, technical repeats). CAL-1 cells were transfected with control siRNA (Contsi) and left unstimulated (n=4, technical repeats) or stimulated with K-type CpG ODN (n=4, technical repeats).

2016-06-01 | E-GEOD-70429 | biostudies-arrayexpress

Tlr9 deficiency in B cells leads to obesity by modulating the immune system and gut microbiota

Project description:We generate B-cell-specific Tlr9-deficient (Tlr9fl/fl/Cd19Cre+/-, KO) B6 mice and model obesity using a high-fat diet. Compared with control mice, B cell Tlr9-deficient mice exhibited increased weight gain, impaired glucose and insulin tolerance, reduced IL-10-producing B cells and increased inflammation in fat tissues. Tlr9 deficiency affected B cell differentiation, immunoglobulin levels, and T cell subsets. Furthermore, altered gut microbiota in B-cell-specific Tlr9-deficient mice led to a pro-inflammatory status in gut associated lymphoid tissues and glucose metabolism dysregulation. Using 16S rRNA sequencing we report altered gut microbial communities in the KO mice. Indeed, a reduction in Lachnospiraceae, may play a key role in the observed metabolic phenotypes in KO mice. Also, We identify an important network involving Tlr9, Irf4 and Il-10.

2024-04-11 | GSE263396 | GEO

RNA-seq analysis of follicular (FO), marginal zone (MZ) and aged-associated B cells (ABC) across three TLR9 genotypes (TLR9WT, TLR9-/- and non-signaling TLR9P915H/P915H) isolated from a mixed chimeric setting in the MRL/lpr murine model of SLE

Project description:Purpose: The goal of this study was to assess if TLR9 deficiency (TLR9-/-) or TLR9 incapacity to signal through MyD88 would differentially influence the gene programs of B cell subsets, in a B cell intrinsic manner. Methods : Mixed bone marrow chimeras of one-third each TLR9+/+ CD45.1/2, TLR9-/- CD45.1/1 and TLR9P915H/P915H CD45.2/2 were generated on the MRL/lpr background. From each recipient, three B cell subsets, FO, MZ and ABC were sorted with respect to the CD45 congenic markers at [x weeks] post chimerism. RNA was isolated using the RNeasy Plus Micro Kit (QIAGEN). Samples were sequenced using NovaSeq 6000 flowcell (Illumina, Inc, California, USA) with 100 bp paired-end reads (20 million reads per sample) and aligned to the mm10 genome using the STAR aligner. Results: ABCs showed the most transcriptional differences among TLR9 genotypes. TLR9P915H and TLR9WT ABC transcriptomes were much more similar to each other than to those of TLR9-/- mice, sharing 246 of 381 DEGs, even though TLR9P915H B cells could not signal via MyD88. These included a number of genes encoding for inhibitory or anti-inflammatory pathways, suggesting that TLR9 could induce a regulatory signal independently of MyD88.

2022-08-03 | GSE181283 | GEO

Effect of CXCL4 on TLR9-induced B cells

Project description:CXCL4 is a cationic peptide that binds to TLR9-ligand oligonucleotide, resulting in an inhibition of TLR9 response in B cells

2023-06-27 | GSE227639 | GEO

Genome-wide maps of Egr2 transcription factor binding sites in NKT and anti TCRb injected thymocytes.

Project description:We report the application of single-molecule-based sequencing technology for mapping the Egr2 transcriptional program in developing thymic NKT. We found that Egr2 controls the induction of genes required for NKT development. Examination of developing NKT cells and thymocytes receiving a strong TCR signal in vivo by injecting 500ug anti-TCRb antibody.

2012-02-06 | E-GEOD-34254 | biostudies-arrayexpress

Formation of Memory Assemblies through the DNA Sensing Tlr9 Pathway

Project description:As hippocampal neurons respond to diverse types of information a subset assembles into stable microcircuits representing a memory. Those neurons typically undergo energy-intensive molecular adaptations, which occasionally results in transient DNA damage. We found, however, discrete clusters of excitatory hippocampal CA1 neurons showing persistent dsDNA breaks, nuclear envelope ruptures, and perinuclear release of histone and dsDNA fragments for hours after learning. Following these early events, some neurons acquired an inflammatory phenotype involving activation of Toll-like receptor 9 (Tlr9) signaling and accumulation of centrosomal DNA damage repair (DDR) complexes. Neuron-specific knockdown of Tlr9 impaired memory while blunting CFC-induced changes of gene expression in specific clusters of excitatory CA1 neurons. Most notably, Tlr9 played an essential role in centrosome function, including DDR, ciliogenesis, and build-up of perineuronal nets (PNN). We demonstrate a novel cascade of learning-induced molecular events in discrete neuronal clusters undergoing dsDNA damage and Tlr9-mediated repair, resulting in their recruitment to memory circuits. With compromised Tlr9 function, this fundamental memory mechanism becomes a gateway to genomic instability and cognitive impairments, which have been implicated in accelerated senescence, psychiatric disorders, and neurodegenerative disorders. Maintaining the integrity of Tlr9 inflammatory signaling thus emerges as a promising preventive strategy for neurocognitive deficits.

2024-03-01 | GSE254780 | GEO

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