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Transcriptome analysis of Bcl11b-deficient regulatory T cells at steady state

ABSTRACT: T regulatory (Treg) cells have been studied in depth since their discovery for their potential use in therapies of autoimmune diseases. Treg cells have a suppression program that includes surface molecules CD25 (IL2R), cytotoxic T-lymphocyte associated protein 4 (CTLA4), and glucocorticoid-induced TNFR family (GITR) to limit aberrant and excessive inflammatory immune responses. We have shown that Bcl11b can bind to the CNS2 region in Foxp3 as well as the gene loci of those essential surface molecules for Treg suppression. Furthermore, we have identified a subset of Foxp3-independent genes in Treg cells directly regulated by Bcl11b binding. Bcl11b also directly represses expression of innate molecules such as transcription factors PU.1 and ID2 in Treg cells. Finally, we have also shown that removal of Bcl11b accelerates apoptosis in Treg cells as cleaved caspase 3 levels were significantly elevated in Bcl11b KO Treg cells when compared with WT Treg cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE120874 | GEO | 2019/08/07

REPOSITORIES: GEO

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Genome wide mapping of chromatin accessibility in Treg cells at steady state

Project description:T regulatory (Treg) cells have been studied in depth since their discovery for their potential use in therapies of autoimmune diseases. Treg cells have a suppression program that includes surface molecules CD25 (IL2R), cytotoxic T-lymphocyte associated protein 4 (CTLA4), and glucocorticoid-induced TNFR family (GITR) to limit aberrant and excessive inflammatory immune responses. We have shown that Bcl11b can bind to the CNS2 region in Foxp3 as well as the gene loci of those essential surface molecules for Treg suppression. Furthermore, we have identified a subset of Foxp3-independent genes in Treg cells directly regulated by Bcl11b binding. Bcl11b also directly represses expression of innate molecules such as transcription factors PU.1 and ID2 in Treg cells. Finally, we have also shown that removal of Bcl11b accelerates apoptosis in Treg cells as cleaved caspase 3 levels were significantly elevated in Bcl11b KO Treg cells when compared with WT Treg cells.

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Mapping Bcl11b binding in human regulatory T cells

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Conserved non-coding sequence 2 (CNS2) of the Foxp3 genomic locus is essential for the function and stability of regulatory T cells during their activation

Project description:Regulatory T (Treg) cells play an indispensable role in immune homeostasis. The development and function of Tregs are dependent on transcriptional factor Foxp3, but how constant expression of Foxp3 is maintained in Tregs is not clear. Here we show that ablation of the conserved non-coding DNA sequence 2 (CNS2) at the Foxp3 locus in mice led to spontaneous lymphoproliferative disease and exacerbation of experimental autoimmune encephalomyelitis (EAE). CNS2 is required for activated Treg cells to maintain elevated Foxp3 expression, which is critical for their suppressor function and lineage stability. Mechanistically, upon TCR stimulation, NFAT binds to both CNS2 and Foxp3 promoter and mediates the interaction between CNS2 and Foxp3 promoter. Our findings demonstrated an essential role for CNS2 in maintaining the stability and function of activated Treg cells and identified NFAT as a key mediator of its function. Gene expression was profiled in T regulatory cells (Treg) in WT and CNS2 knockout mice. CNS2 knockout mice lack a conserved non-coding DNA sequence 2 (CNS2) at the Foxp3 locus. Treg cells were further sorted into Foxp3-high and Foxp3-low populations based on the expression level of Foxp3. mRNA was profiled using RNA-Seq (unstranded, polyA+, SE100) in replicate for each condition

2014-09-04 | E-GEOD-57272 | biostudies-arrayexpress

Tregs from Bcl11b-deficient versus wild type Tregs (CD4Cre and Foxp3Cre systems)

Project description:expression profile in Bcl11b-deficient Treg cells versus wild type Treg cells Treg cells sorted from Bcl11bF/F/Cd4Cre/Foxp3-GFP+ mice and wild type Foxp3-GFP+ mice Treg cells sorted from Bcl11bF/F/Foxp3Cre mice and wild type mice RNA extracted from sorted Bcl11b-deficient Foxp3-GFP Treg cells form Bcl11bF/F/Cd4Cre/Foxp3-GFP+ mice and wild type Foxp3-GFP Treg cells; expression profile by microarray analysis RNA extracted from sorted Bcl11b-deficient Treg cells form Bcl11bF/F/Foxp3Cre mice and wild type Treg cells; expression profile by microarray analysis

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Conserved non-coding sequence 2 (CNS2) of the Foxp3 genomic locus is essential for the function and stability of regulatory T cells during their activation

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Bcl11b prevents catastrophic autoimmunity by controlling multiple aspects of regulatory T-cell gene expression program [ChIP-Seq]

Project description:In order to identify Bcl11b-bound sites in Treg cells(WT) and Tn cells and to determine Bcl11n and Foxp3 peak overlaps, we performed Bcl11b and Foxp3 ChIP-seq on respective cell populations. In order to understand whether Bcl11b recruitment to it's target sites is dependent on Foxp3 we performed Bcl111b ChIP-Seq in Tfn cells(derived from Foxp3GFPKO mice). Finally, to ask whether genome-wide occupancy of Foxp3 is affected in the absence of Bcl11b, we performed Foxp3 ChIP-seq in Bcl11b-deficient Treg cells(KO Treg).

2019-08-07 | GSE120947 | GEO

MicroRNA profiling of mouse T regulatory cells (Tregs) reveals miRNA disruption in Tregs leads to uncontrolled autoimmunity

Project description:A new Treg-specific, FoxP3-GFP-hCre BAC transgenic was crossed to a conditional Dicer knock-out mouse strain to analyze the role of microRNAs (miRNA) in the development and function of regulatory T cells (Tregs). Although thymic Tregs developed normally in this setting, the cells showed evidence of altered differentiation and dysfunction in the periphery. Dicer-deficient Treg lineage cells failed to remain stable as a subset of cells down-regulated the Treg-specific transcription factor, FoxP3, while the majority expressed altered levels of multiple genes and proteins (including Neuropilin 1, GITR and CTLA-4) associated with the Treg fingerprint. In fact, a significant percentage of the Treg lineage cells took on a Th memory phenotype including increased levels of CD127, IL-4, and interferon-g. Importantly, Dicer-deficient Tregs lost suppression activity in vivo; the mice rapidly developed fatal systemic autoimmune disease resembling the FoxP3 knockout phenotype. These results support a central role for miRNAs in maintaining the stability of differentiated Treg function in vivo and homeostasis of the adaptive immune system. Experiment Overall Design: Lymph node CD4+YFP+ T cells from FoxP3-GFP-hCre x ROSA26R-YFP Dicerwt/lox (Het) and FoxP3-GFP-hCre x ROSA26R-YFP Dicerlox/lox (KO) mice were isolated by flow cytometry. Triplicate GeneChips were used for each T cell population.

2008-10-21 | E-GEOD-11818 | biostudies-arrayexpress

Blimp1 maintains regulatory T cell identity at sites of inflammation through epigenetic imprinting

Project description:Foxp3+ regulatory T (Treg) cells restrict immune pathology in inflamed tissues; however, an inflammatory environment presents a threat to Treg cell identity and function. We here establish a transcriptional signature of central nervous system (CNS) Treg cells that accumulate during experimental autoimmune encephalitis (EAE) and identify a pathway that maintains Treg cell function and identity during severe inflammation. This pathway was dependent on the transcriptional regulator Blimp1, which prevented dismantling of Foxp3 expression and "toxic" gain-of-function of Treg cells in the inflamed CNS. Blimp1 negatively regulated IL-6- and STAT3-mediated methylation of Treg cell-specific conserved non-coding sequence 2 (CNS2) in the Foxp3 locus. Consequently, CNS2 was heavily methylated when Blimp1 was ablated, leading to loss of Foxp3 expression and severe disease. These findings identify a Blimp1-dependent epigenetic pathway that preserves Treg cell stability in inflamed non-lymphoid tissues.

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mRNA expression in CD4+ CD25+ GITR+ regulatory T cells from WT and Bach2 KO mice

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2013-11-14 | E-GEOD-52337 | biostudies-arrayexpress

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