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FoxP3 scanning mutagenesis reveals functional variegation and mild mutations with atypical autoimmune phenotypes [microarray]

ABSTRACT: Microarray profiles of M176, M354 and WT FoxP3 -transdued (in vitro) and -Treg from mice

ORGANISM(S): Mus musculus

PROVIDER: GSE104345 | GEO | 2017/09/28

SECONDARY ACCESSION(S): PRJNA412401

REPOSITORIES: GEO

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FoxP3 scanning mutagenesis reveals functional variegation and mild mutations with atypical autoimmune phenotypes [nanostring]

Project description:Nanostring profiles of CD4+ T cells transduced with EV, WT or FoxP3 mutants

2017-09-28 | GSE104344 | GEO

FoxP3 scanning mutagenesis reveals functional variegation and mild mutations with atypical autoimmune phenotypes.

Project description:FoxP3+ regulatory T cells (Tregs) are a central element of immunological tolerance. FoxP3 is the key determining transcription factor of the Treg lineage, interacting with numerous cofactors and transcriptional targets to determine the many facets of Treg function. Its absence leads to devastating lymphoproliferation and autoimmunity in scurfy mutant mice and immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) patients. To finely map transcriptionally active regions of the protein, with respect to disease-causing variation, we performed a systematic alanine-scan mutagenesis of FoxP3, assessing mutational impacts on DNA binding and transcriptional activation or repression. The mutations affected transcriptional activation and repression in a variegated manner involving multiple regions of the protein and varying between different transcriptional targets of FoxP3. There appeared to be different modalities for target genes related to classic immunosuppressive function vs. those related to atypical or tissue-Treg functions. Relevance to in vivo Treg biology was established by introducing some of the subtle Foxp3 mutations into the mouse germline by CRISPR-based genome editing. The resulting mice showed Treg populations in normal numbers and exhibited no overt autoimmune manifestations. However, Treg functional defects were revealed upon competition or by system stress, manifest as a strikingly heightened susceptibility to provoked colitis, and conversely by greater resistance to tumors. These observations suggest that some of the missense mutations that segregate in human populations, but do not induce IPEX manifestations, may have unappreciated consequences in other diseases.

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FoxP3 scanning mutagenesis reveals functional variegation and mild mutations with atypical autoimmune phenotypes

Project description:This SuperSeries is composed of the SubSeries listed below.

2017-09-28 | GSE104346 | GEO

FoxP3 scanning mutagenesis reveals functional variegation and mild mutations with atypical autoimmune phenotypes

Project description:FoxP3 scanning mutagenesis reveals functional variegation and mild mutations with atypical autoimmune phenotypes

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FoxP3 scanning mutagenesis reveals functional variegation and mild mutations with atypical autoimmune phenotypes [microarray]

Project description:FoxP3 scanning mutagenesis reveals functional variegation and mild mutations with atypical autoimmune phenotypes [microarray]

| PRJNA412401 | ENA

FoxP3 scanning mutagenesis reveals functional variegation and mild mutations with atypical autoimmune phenotypes [nanostring]

Project description:FoxP3 scanning mutagenesis reveals functional variegation and mild mutations with atypical autoimmune phenotypes [nanostring]

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Punctual ablation of Foxp3+ T cells unleashes an autoimmune lesion

Project description:How do Treg cells control an autoimmune lesion? We depleted Foxp3+ Treg cells in autoimmune prone TCR transgenic BDC2.5 mice on the NOD background Kinetic of gene-expression changes in CD4 T cells isolated for pancreas and pancreas draining lymph node (PLN) of Foxp3-DTR.BDC2.5/NOD mice after Treg cell ablation Keywords: T cell activation/ differentiation after Treg depletion timecourse CD4 T cells were isolated from pancreas and PLN at 0, 15 and 24 hours after diphtheria toxin application into 4-6 week old female Foxp3-DTR.BDC2.5/NOD transgenic mice

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Foxp3 positive and negative cell comparison

Project description:Regulatory T cells have been shown to adopt a catabolic metabolic programme with increased capacity for fatty acid oxidation fuelled oxidative phosphorylation (OXPHOS). The role of Foxp3 in this metabolic shift is poorly understood. Here we show that Foxp3 was sufficient to induce a significant increase in the spare respiratory capacity of the cell, the extra OXPHOS capacity available to a cell to increased demands on energy in response to work. Foxp3-expressing cells were enhanced in their ability to utilise palmitate for respiration and in addition the activity of electron transport complexes I, II and IV were enhanced following Foxp3 expression. ATP was secreted by both T effector and regulatory T cells and was reduced by mitochondrial respiration inhibitors. Thus Foxp3 imparts a selective advantage in ATP generation capacity to the cell and may exploit this as a source of adenosine for functional immunomodulation. In order to explore possible mechanisms for these differences in metabolism we conducted a comparative quantitative proteomics study to compare the contribution of TGFβ and the transcription factor Foxp3 to the Treg proteome. We used quantitative mass spectrometry to examine differences between proteomes of nuclear and cytoplasmic Foxp3-containing T cells and Foxp3 positive iTreg and Foxp3 negative activated CD4 T cells in addition to human peripheral blood natural Treg. Gene set enrichment analysis of our proteomic datasets demonstrated that Foxp3 drives a significant up regulation of several members of the mitochondrial electron transport chain.

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Alanine-scanning mutagenesis of Aspergillus gamma-tubulin yields diverse and novel phenotypes.

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