Background. T cells in the thymus undergo opposing positive and negative selection processes so that the only T cells entering circulation are those bearing a T cell receptor (TCR) with a low affinity for self. The mechanism differentiating negative from positive selection is poorly understood, despite the fact that inherited defects in negative selection underlie organ-specific autoimmune disease in AIRE-deficient people and the non obese diabetic (NOD) mouse strain. Results. Here we use homogeneous populations of T cells undergoing either positive or negative selection in vivo together with genome-wide transcription profiling on microarrays to identify the gene expression differences underlying negative selection to an Aire-dependent organ-specific antigen, including the upregulation of a genomic cluster in the cytogenetic band 2F. Analysis of defective negative selection in the autoimmune-prone NOD strain demonstrates a global impairment in the induction of the negative selection response gene set, but little difference in positive selection response genes. Combining expression differences with genetic linkage data we identify differentially expressed candidate genes including Bim, Bnip3, Smox, Pdrg1, Id1, Pdcd1, Ly6c, Pdia3, Trim30 and Trim12. Conclusions. The data provide a molecular map of the negative selection response in vivo, and by analysis of deviations from this pathway in the autoimmune susceptible NOD strain, suggest that susceptibility arises from small expression differences in genes acting at multiple points in the pathway between the TCR and cell death.
Impairment of organ-specific T cell negative selection by diabetes susceptibility genes: genomic analysis by mRNA profiling.
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View SamplesIgG cytoplasmic tail interferes with the induction of antigen-response genes
Enhancement and suppression of signaling by the conserved tail of IgG memory-type B cell antigen receptors.
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View SamplesThis SuperSeries is composed of the SubSeries listed below.
Zinc finger protein Zfp335 is required for the formation of the naïve T cell compartment.
Specimen part
View SamplesThe wider transcriptional effects of MYD88L265P were explored by analysing the microarray datasets using the limma package. We focussed on evidence for differential expression between Myd88L265P and Card11L232LI transduced B cells because both cell populations were actively proliferating at the time of RNA isolation.
Synergistic cooperation and crosstalk between <i>MYD88<sup>L265P</sup></i> and mutations that dysregulate CD79B and surface IgM.
Specimen part
View SamplesThe generation of nave T lymphocytes is critical for immune function yet the mechanisms governing their maturation remain incompletely understood. We have identified a mouse mutant, bloto, that harbors a hypomorphic mutation in the zinc finger protein Zfp335. Mutant blt/blt mice exhibit a nave T cell deficiency due to an intrinsic developmental defect that begins to manifest in the thymus and continues into the periphery, affecting T cells that have recently undergone thymic egress. Zfp335 binds to promoter regions via a consensus motif, and its target genes are enriched in categories related to protein metabolism, mitochondrial function and transcriptional regulation. Restoring the expression of one target, Ankle2, partially rescues T cell maturation. Our findings identify Zfp335 as a transcription factor and essential regulator of late-stage intrathymic and post-thymic T cell maturation.
Zinc finger protein Zfp335 is required for the formation of the naïve T cell compartment.
Specimen part
View SamplesThe generation of nave T lymphocytes is critical for immune function yet the mechanisms governing their maturation remain incompletely understood. We have identified a mouse mutant, bloto, that harbors a hypomorphic mutation in the zinc finger protein Zfp335. Mutant blt/blt mice exhibit a nave T cell deficiency due to an intrinsic developmental defect that begins to manifest in the thymus and continues into the periphery, affecting T cells that have recently undergone thymic egress. Zfp335 binds to promoter regions via a consensus motif, and its target genes are enriched in categories related to protein metabolism, mitochondrial function and transcriptional regulation. Restoring the expression of one target, Ankle2, partially rescues T cell maturation. Our findings identify Zfp335 as a transcription factor and essential regulator of late-stage intrathymic and post-thymic T cell maturation.
Zinc finger protein Zfp335 is required for the formation of the naïve T cell compartment.
Specimen part
View SamplesSelection of B cells subjected to hypermutation in germinal centres (GC) during T-dependent (TD) antibody responses yields memory cells and long-lived plasma cells that produce high affinity antibodies biased to foreign antigens rather than self-antigens. GC also form in T-independent (TI) responses to polysaccharide antigens but failed selection results in GC involution and memory cells are not generated. To date there are no markers that allow phenotypic distinction of T-dependent and T-independent germinal centre B cells. We have now compared the global gene expression of GC B cells purified from mice immunized with either TD or TI antigens and identified eighty genes that are differentially expressed in TD GC.
Axon growth and guidance genes identify T-dependent germinal centre B cells.
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View SamplesMale C57BL/6 mice were treated with ENU to generate single base substitutions, the variant genome sequences were breed to homozygosity in inbreeding pedigrees, and screened for antinuclear autoantibodies (ANA). The sanroque pedigree contained multiple progeny with ANA of mixed homogeneous nuclear and cytoplasmic immunofluorescence pattern by 12 weeks of age, due to an autosomal recessive gene variant. Comparison of the gene expression profile of CD4 cells from Sanroque to wild type was performed.
A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity.
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View SamplesA major role of NINJA is to repress root jasmonate signalling and allow normal cell elongation.
Multilayered Organization of Jasmonate Signalling in the Regulation of Root Growth.
Specimen part
View SamplesThe traditional view of hematopoiesis has been that all the cells of the peripheral blood are the progeny of a unitary homogeneous pool of hematopoietic stem cells (HSCs). Recent evidence suggests that the hematopoietic system is actually maintained by a consortium of HSC subtypes with distinct functional characteristics. We show here that myeloid-biased HSCs (My-HSCs) and lymphoid-biased (Ly-HSCs) can be purified according to their capacity for Hoechst dye efflux in combination with canonical HSC markers.
Distinct hematopoietic stem cell subtypes are differentially regulated by TGF-beta1.
Sex, Specimen part
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