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GSE37783
Homo sapiens
6 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Natalizumab is a recombinant monoclonal antibody raised against integrin alpha-4 (CD49d). It is approved for the treatment of patients with multiple sclerosis (MS), a chronic inflammatory autoimmune disease of the CNS. Natalizumab blocks leukocyte extravasation across the blood-brain barrier by inhibiting the molecular interaction between integrin alpha-4/beta-1 heterodimers expressed on leukocytes and VCAM-1 on inflammatory-activated CNS endothelium. Here we investigated whether binding of this adhesion-blocking antibody to T lymphocytes modulated their phenotype by direct induction of intracellular signaling events. Natalizumab induced a mild upregulation of IL-2, IFN-gamma and IL-17 expression in activated primary human CD4+ T cells propagated ex vivo from healthy donors, consistent with a pro-inflammatory costimulatory effect on lymphokine expression. Overall, the relative effect of natalizumab was more pronounced in less than in fully activated T cells. Along with this, natalizumab binding triggered rapid MAPK/ERK phosphorylation. Furthermore, it decreased CD49d surface expression on effector cells within a few hours. Sustained CD49d downregulation could be attributed to integrin internalization and degradation. Importantly, also CD4+ T cells from some MS patients receiving their very first dose of natalizumab produced more IL-2, IFN-gamma and IL-17 already 24 h after infusion. Together these data indicate that in addition to its adhesion-blocking mode of action, natalizumab possesses mild direct signaling capacities, which may support a pro-inflammatory phenotype of peripheral blood T lymphocytes. This might explain why a rebound of disease activity is observed in some MS patients after natalizumab cessation.
Publication Title
Natalizumab exerts direct signaling capacity and supports a pro-inflammatory phenotype in some patients with multiple sclerosis.
Sample Metadata Fields
Specimen part, Disease, Disease stage, Treatment
View Samples- Mus musculus
- 16 Downloadable Samples
Illumina HiSeq 2500
Description
T follicular helper (TFH) cells promote affinity maturation of B cells in germinal centers (GCs), whereas T follicular regulatory (TFR) cells limit GC reaction. Store-operated Ca2+ entry (SOCE) through Ca2+ release-activated Ca2+ (CRAC) channels mediated by STIM and ORAI proteins is a fundamental signaling pathway in T lymphocytes. Here we show that SOCE is required for the differentiation and function of both TFH and TFR cells. Conditional deletion of Stim1 and Stim2 genes in T cells or Treg cells results in spontaneous autoantibody production and humoral autoimmunity. Conversely, antibody-mediated immune responses following viral infection critically depend on SOCE in TFH cells. Mechanistically, STIM1 and STIM2 control early TFR and TFH cell differentiation through NFAT-mediated IRF4, BATF and Bcl-6 expression. SOCE plays a dual role in GC response by controlling TFH and TFR cell function, thus enabling protective B cell responses and preventing humoral autoimmunity. Overall design: RNAseq analyses of WT and Stim1Stim2 DKO follicular T cells and non-follicular T cells; 4-6 mice per cohort in duplicates. Mice were infected for 10 days with LCMV.
Publication Title
Store-Operated Ca(2+) Entry in Follicular T Cells Controls Humoral Immune Responses and Autoimmunity.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 33 Downloadable Samples
- NextSeq 500, Illumina HiSeq 2000
Description
During chronic stimulation T cells acquire an exhausted phenotype characterized by expression of multiple inhibitory receptors and down-modulation of effector function. While this is required for the protection of the organism from excessive immunopathology, it also prevents successful immunity against persistent viruses or tumor cells. Here we demonstrate that CD8+ T cell exhaustion is characterized by a progressive decline in cellular metabolism. Exhausted T cells exhibit reduced metabolic reserve, impaired fatty acid oxidation and production of mitochondrial reactive oxygen species (ROS). Blockade of inhibitory PD-1/PD-L1 signaling rescued mitochondrial biogenesis, oxidative phosphorylation and ROS production, which was required for efficient restoration of cellular expansion and effector function. Expression of inhibitory receptors and impaired metabolic function was fuled by high amounts of IRF4, BATF and NFAT, which formed a TCR-responsive transcriptional circuit that sustained the transcriptional network responsible for T cell exhaustion. Overall design: Transcriptional profiling of T cells in mice with chronic and acute infections using RNA sequencing
Publication Title
Transcription Factor IRF4 Promotes CD8<sup>+</sup> T Cell Exhaustion and Limits the Development of Memory-like T Cells during Chronic Infection.
Sample Metadata Fields
Specimen part, Cell line, Subject, Time
View Samples- Homo sapiens
- 12 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Anaplastic lymphoma kinase (ALK) is expressed in around 60% of glioblastomas and conveys tumorigenic function. Therefore, ALK inhibitory strategies with alectinib were investigated in glioblastoma cells. We demonstrated that alectinib inhibited proliferation and clonogenicity of ALK expressing glioblastoma initiating cells, whereas cells without ALK expression or after ALK depletion via knockdown showed primary resistance against alectinib. The aim of this analysis was to investigate molecular mechanisms of alectinib mediated treatment effects in the ALK expressing S24 cells, which represent a primary glioblastoma cell culture, and after knockdown of ALK.
Publication Title
cMyc and ERK activity are associated with resistance to ALK inhibitory treatment in glioblastoma.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Mus musculus
- 6 Downloadable Samples
- Illumina HiSeq 2500
Description
Goal of this study was to compare transcriptional changes in IFN-gamma-treated WT compared to IRF1-deficient Th9 cells Overall design: mRNA profiles of Th9 cells cultured for 2 days in the presence of IFN-gamma in vitro were generated by deep sequencing using Illumina HiSeq2000
Publication Title
Reciprocal regulation of the Il9 locus by counteracting activities of transcription factors IRF1 and IRF4.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 24 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Triggering of B cell receptors (BCR) induces a massive synthesis of NFATc1 in splenic B cells. By inactivating the Nfatc1 gene and re-expressing NFATc1 we show that NFATc1 levels are critical for the survival of splenic B cells upon BCR stimulation. NFATc1 ablation led to decreased BCR-induced Ca++ flux and proliferation of splenic B cells, increased apoptosis and suppressed germinal centre formation and immunoglobulin class switch by T cell-independent antigens. By controlling IL-10 synthesis in B cells, NFATc1 supported the proliferation and IL-2 synthesis of T cells in vitro and appeared to contribute to the mild clinical course of Experimental Autoimmune Encephalomyelitis in mice bearing NFATc1-/- B cells. These data indicate NFATc1 as a key factor controlling B cell function.
Publication Title
NFATc1 affects mouse splenic B cell function by controlling the calcineurin--NFAT signaling network.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 17 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
The aim of this experiment was to investigate the dysregulation of gene expression in whole E12.5 embryos containing a gene trap (CH) or point mutation (H275R) within the Klf3 gene
Publication Title
ENU-induced mutation in the DNA-binding domain of KLF3 reveals important roles for KLF3 in cardiovascular development and function in mice.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 36 Downloadable Samples
- Affymetrix Human Gene 2.1 ST Array (hugene21st)
Description
Targets of Retinoic Acid (RA) and 3,4-didehydroretinoic acid (ddRA) were identified in primary human epidermal keratinocytes grown in the presence of atRA or ddRA for 4 and 24 hours.
Publication Title
The effect of two endogenous retinoids on the mRNA expression profile in human primary keratinocytes, focusing on genes causing autosomal recessive congenital ichthyosis.
Sample Metadata Fields
Treatment
View Samples- Danio rerio
- 2 Downloadable Samples
- IlluminaHiSeq2000
Description
Purpose: using RNA-seq as a screening tool to determine candidate genes of interest within a genetically defined neural subpopulation in the zebrafish embryonic spinal cord. Results: The early embryonic spinal cord displays patterns of spontaneous activity that generate the earliest motor behavior in the zebrafish. We show the behavior and the neural activity to be inhibited by environmental levels of light. Since at these young ages the fish is blind, and since restricted illumination patterns on the trunk of the fish can elicit a photo-response, we hypothesized that the photo-inhibition is an intrinsic property of the active central pattern generator network within the spinal cord. We FACS-isolated cells from this network as well as those from a panneuronal population and sequenced mRNAs. Through differential expression analysis we identified vertebrate ancient long opsin a as a candidate and then further validated its function in the circuit through knockdown and rescue experiments. Overall design: RNA sequencing of 2 FACS purified neural populations from zebrafish spinal cord.
Publication Title
A spinal opsin controls early neural activity and drives a behavioral light response.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 14 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
The adaptor protein Lnk is an important negative regulator of HSC homeostasis and self-renewal. This study aims to investigate the role of Lnk in HSC aging. Here we performed expression profiling of bone marrow CD150+CD48-LSK LT-HSCs from young and old WT and Lnk-/- mice. Results identify select Lnk-mediated pathways with potential involvement in HSC self-renewal and aging.
Publication Title
Lnk deficiency partially mitigates hematopoietic stem cell aging.
Sample Metadata Fields
Specimen part
View Samples