Helios KO Tregs
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ABSTRACT:
PROVIDER: PRJNA746796 | ENA |
REPOSITORIES: ENA
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Project description:The maintenance of immune homeostasis requires regulatory T cells (Tregs). Given their intrinsic self-reactivity, Tregs must stably maintain a suppressive phenotype to avoid autoimmunity. We report that impaired expression of the transcription factor (TF) Helios by FoxP3+ CD4 and Qa-1-restricted CD8 Tregs results in defective regulatory activity and autoimmunity in mice. Helios-deficient Treg develop an unstable phenotype during inflammatory responses characterized by reduced FoxP3 expression and increased effector cytokine expression secondary to diminished activation of the STAT5 pathway. CD8 Treg also require Helios-dependent STAT5 activation for survival and to prevent terminal T cell differentiation. Definition of Helios as a key transcription factor that stabilizes regulatory T-cells in the face of inflammatory responses provides a genetic explanation for a core property of regulatory T-cells.
2015-10-16 | GSE72997 | GEO
Project description:Transcriptional comparison of WT Tregs versus MOG KO Tregs
2016-08-31 | GSE79124 | GEO
Project description:The maintenance of immune homeostasis requires regulatory T cells (Tregs). Given their intrinsic self-reactivity, Tregs must stably maintain a suppressive phenotype to avoid autoimmunity. We report that impaired expression of the transcription factor (TF) Helios by FoxP3+ CD4 and Qa-1-restricted CD8 Tregs results in defective regulatory activity and autoimmunity in mice. Helios-deficient Treg develop an unstable phenotype during inflammatory responses characterized by reduced FoxP3 expression and increased effector cytokine expression secondary to diminished activation of the STAT5 pathway. CD8 Treg also require Helios-dependent STAT5 activation for survival and to prevent terminal T cell differentiation. Definition of Helios as a key transcription factor that stabilizes regulatory T-cells in the face of inflammatory responses provides a genetic explanation for a core property of regulatory T-cells. We used microarrays to detail the global programs of gene expression by CD8 Treg (CD44+CD122+Ly49+) and conventional memory type of CD8 cells (CD44+CD122+Ly49-).
2015-09-15 | E-GEOD-73015 | biostudies-arrayexpress
Project description:The zinc finger transcription factor Helios is critical for maintaining the identity and suppressive phenotype of regulatory T cells (Tregs) and as such is an attractive target to enhance the efficacy of currently approved immunotherapies. However, no small molecules exist which can directly modulate Helios activity or abundance. Here, we report the structure-guided development of novel small molecules capable of inducing neo-interactions between Helios and the E3 ubiquitin ligase substrate adaptor Cereblon (CRBN), thereby promoting Helios degradation. Crystallographic studies reveal that these new compounds accommodate a key histidine residue in the β-hairpin loop of its second zinc finger domain. Finally, pharmacological Helios degradation destabilized the anergic phenotype of regulatory T cells, demonstrating that Helios is a new druggable target that may enhance anti-tumor immunity. Our study provides a road-map for developing small molecule degraders of other difficult-to-drug targets through ligase reprogramming that is complementary to the bi-valent proteolysis targeting chimera (PROTACs) approach.
2021-05-26 | PXD023691 | Pride
Project description:The zinc finger transcription factor Helios is critical for maintaining the identity and suppressive phenotype of regulatory T cells (Tregs) and as such is an attractive target to enhance the efficacy of currently approved immunotherapies. However, no small molecules exist which can directly modulate Helios activity or abundance. Here, we report the structure-guided development of novel small molecules capable of inducing neo-interactions between Helios and the E3 ubiquitin ligase substrate adaptor Cereblon (CRBN), thereby promoting Helios degradation. Crystallographic studies reveal that these new compounds accommodate a key histidine residue in the β-hairpin loop of its second zinc finger domain. Finally, pharmacological Helios degradation destabilized the anergic phenotype of regulatory T cells, demonstrating that Helios is a new druggable target that may enhance anti-tumor immunity. Our study provides a road-map for developing small molecule degraders of other difficult-to-drug targets through ligase reprogramming that is complementary to the bi-valent proteolysis targeting chimera (PROTACs) approach.
2021-05-26 | PXD016168 | Pride
Project description:The maintenance of immune homeostasis requires regulatory T cells (Tregs). Given their intrinsic self-reactivity, Tregs must stably maintain a suppressive phenotype to avoid autoimmunity. We report that impaired expression of the transcription factor (TF) Helios by FoxP3+ CD4 and Qa-1-restricted CD8 Tregs results in defective regulatory activity and autoimmunity in mice. Helios-deficient Treg develop an unstable phenotype during inflammatory responses characterized by reduced FoxP3 expression and increased effector cytokine expression secondary to diminished activation of the STAT5 pathway. CD8 Treg also require Helios-dependent STAT5 activation for survival and to prevent terminal T cell differentiation. Definition of Helios as a key transcription factor that stabilizes regulatory T-cells in the face of inflammatory responses provides a genetic explanation for a core property of regulatory T-cells.
2015-09-15 | GSE73015 | GEO
Project description:Transcriptome of splenic Treg cells (CD4+CD25+) from 7-week old WT and Ikzf2-/- mice (RNA-seq)
2023-10-24 | GSE180159 | GEO
Project description:The transcription factor Helios is expressed in a large subset of Foxp3+ Tregs of both mouse and man. We previously demonstrated that Treg induced in peripheral sites (pTreg) from Foxp3- T conventional (Tconv) cells were Helios- and proposed that Helios is a marker of thymic derived Treg (tTreg). To compare the two Treg subpopulations, we generated Helios-GFP reporter mice and crossed them to Foxp3-RFP reporter mice. The Helios+ Treg population expressed a more activated phenotype and had a higher suppressive capacity in vitro. Both populations expressed a highly demethylated TSDR and both subsets were equivalent in their ability to suppress inflammatory bowel disease in vivo. However, Helios+ Treg more effectively inhibited the proliferation of activated, autoreactive splenocytes from scurfy mice. When Helios+ and Helios- Treg were transferred to lymphoreplete mice, both populations maintained comparable Foxp3 expression, but Foxp3 expression was less stable in Helios- Treg when transferred to lymphopenic mice. Gene expression profiling of the two populations demonstrated a large number of differentially expressed genes and that Helios- Treg subpopulation expressed certain genes normally expressed in CD4+Foxp3- T cells. TCR repertoire analysis indicated very little overlap between Helios+ and Helios- Treg. Thus, Helios+ and Helios- Treg subpopulations are phenotypically and functionally distinct, consistent with thymic and peripheral sites of origin, respectively. Because of their superior suppressive activity and enhanced stability Foxp3+Helios+ Treg represent the optimal Treg population for cellular immunotherapy.
2019-01-24 | GSE117989 | GEO
Project description:To understand the mechanisms through which JunB regulates Tregs-mediated immune regulation, we examined the global gene expression profiles in the JunB WT and KO Tregs by performing RNA sequencing (RNA-seq) analysis.
2019-05-07 | GSE129060 | GEO
Project description:The experiment was designed to compare transcriptomic differences between WT and Ccr6 KO Tregs during activation. WT and Ccr6 KO Tregs, cells were isolated from mice and cultured in vitro for 3 days with activation using anti-CD3/CD28 beads. Total RNA was extracted using the Trizol method. Quantity and quality were assessed using a Thermo Scientific™ NanoDrop™ 2000/2000c Spectrophotometer. Novogene Corporation Inc prepared the RNA-seq 250-300 bp insert cDNA library. Illumina HiSeq platform PE150 sequencing was used for sequencing, yielding 20M raw reads/sample. Mus Musculus mm39 was used as the reference genome for alignment.
2024-08-10 | E-MTAB-14288 | biostudies-arrayexpress