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The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells [array]

ABSTRACT: Using an unbiased chemical biology approach, we discover harmine as a novel regulator of Treg/Th17 differentiation. Harmine enhances Treg differentiation (working in conjunction with low levels of exogenous TGFb) and inhibits Th17 differentiation. Analysis of global gene expression of Tregs generated using low TGFb + harmine reveals significant similarity to Tregs generated using high TGFb only and suggests relevance of harmine-engaged mechanisms to IBD. Naïve CD4+CD62L+ T cells were purified from Foxp3GFP mice either by MACS or FACS, then cultured in either low TGFb + harmine or high TGFb conditions. GFP+ Tregs were sorted by FACS at day 4.

ORGANISM(S): Mus musculus

SUBMITTER: Bernard Khor

PROVIDER: E-GEOD-64247 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells [array]

Project description:Using an unbiased chemical biology approach, we discover harmine as a novel regulator of Treg/Th17 differentiation. Harmine enhances Treg differentiation (working in conjunction with low levels of exogenous TGFb) and inhibits Th17 differentiation. Analysis of global gene expression of Tregs generated using low TGFb + harmine reveals significant similarity to Tregs generated using high TGFb only and suggests relevance of harmine-engaged mechanisms to IBD.

2015-04-29 | GSE64247 | GEO

The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells [seq]

2015-04-29 | GSE67960 | GEO

Tcf1 controls Treg functions that regulate inflammation, CD8 T-cell cytotoxicity, and severity of colon cancer

Project description:Tcf1, the DNA-binding partner of β-catenin, is essential for the development and function of T regulatory cells (Tregs). However, how Tcf1 regulates Treg functional specification is less understood. Here, we ablated Tcf1 in Tregs to elucidate its role in Treg specification in healthy mice and mice with colon cancer. RNAseq and single-cell RNAseq revealed that Tcf1 deficient Tregs maintain their core transcriptional signature and diversity, but promote T-cell receptor, Tgfβ receptor, TH17, and Wnt/β-catenin signaling pathways. Central-memory-Tregs with low Klf2 and effector-Tregs with high Mif expression gain TH17 characteristics and mature into effector Treg subpopulations that strongly express cMaf. Tcf1 deficient Tregs exhibit enhanced suppression of T-cell proliferation and cytotoxicity but are compromised in controlling CD4+ T-cell polarization and inflammation. In mice with polyposis, Tcf1 deficient Tregs promote inflammation and tumor growth. Thus, Tcf1 determines Treg functions that regulate TH17 inflammation and the course and outcome of colorectal cancer.

2021-06-01 | GSE163084 | GEO

CD49f defines a subset of dysfunctional regulatory T cells circulating in the human peripheral blood

Project description:The therapeutic use of regulatory T cells (Tregs) in patients with autoimmune disorders has been hampered by the biological variability of memory Treg populations in the peripheral blood. In this study, we reveal through a combination of quantitative proteomic, multiparametric flow cytometry, RNA-seq data analysis and functional assays, that CD49f is heterogeneously expressed among human Tregs and impacts their immunomodulatory function. High expression of CD49f defines a subset of dysfunctional Tregs in the human blood characterized by a Th17-like phenotype and impaired suppressive capacity. CD49f is similarly distributed between naïve and memory Tregs and impacts the expression of CD39, CTLA-4, FoxP3 and CCR6 specifically in the memory compartment. Accumulation of CD49f high memory Tregs in the blood of ulcerative colitis patients correlates with disease severity. Our results highlight important considerations for Treg immunotherapy design in patients with inflammatory bowel disease which could possibly extend to other autoimmune disorders.

2021-08-06 | PXD022095 | Pride

Transcriptome and translatome of human regulatory T cells differentiated with TGFbeta and mTOR inhibitor everolimus

Project description:Regulatory T cells (Tregs) inhibit effector T cells and maintain immune system homeostasis. Treg maturation in peripheral sites (pTregs) is poorly understood but is known to require inhibition of protein kinase mTORC1 (e.g.RAD001) and exposure to TGFb. Paradoxically, Treg maturation requires protein synthesis yet mTORC1 inhibition downregulates it, leaving unanswered how Tregs carry-out essential mRNA translation for development and immune suppression activity. Using human CD4+ T cells differentiated in culture (iTregs) and genome-wide transcription and translation profiling, we show that TGFb transcriptionally reprograms naïve T cells to express iTreg differentiation and immune suppression mRNAs, while mTORC1 inhibition impairs translation of T cell mRNAs but not those induced by TGFb. TGFb-induced Treg mRNAs were found to utilize an alternate mechanism for cap-dependent mRNA translation directed by the DAP5/eIF3d complex rather than canonical mTORC1/eIF4E during Treg development, which is directed by their 5’-untranslated regions. iTreg differentiation is therefore mediated by combined TGFb transcriptional and translational reprogramming and a privileged mechanism of mRNA translation

2021-06-22 | GSE178634 | GEO

Loss of Foxp3-driven epigenetic modification leads to regulatory T cell insufficiency

Project description:Regulatory T cells (Tregs) are responsible for limiting autoimmunity and chronic inflammation. Foxp3 is a transcription factor that acts as a master regulator of Treg development and function. A serendipitous observation led to the realization that a well-characterized Foxp3gfp reporter mouse, which expresses an N-terminal GFP-Foxp3 fusion protein, is a hypomorph that causes profoundly accelerated autoimmune diabetes on a NOD background. Although natural Treg development and in vitro function is not significantly altered in Foxp3gfp NOD and C57BL/6 mice, Treg fitness function in inflammatory environments is perturbed and TGF?-induced Treg development reduced. Foxp3gfpis unable to interact with the histone acetyltransferase Tip60, the histone deacetylase HDAC7, and the Ikaros family zinc finger 4, Eos, which leads to reduced Foxp3 acetylation and enhanced K48-linked polyubiquitylation. Collectively this leads to an altered transcriptional landscape and reduced Foxp3-mediated gene repression, notably at the hallmark IL-2 promoter. Loss of controlled Foxp3-driven epigenetic modification leads to Treg insufficiency that causes autoimmunity in prone environments. 16 samples overall split between 2 genotypes (wild type and Foxp3 knock in) and two cell types (Tregs and Tconv)

2012-12-07 | E-GEOD-35164 | biostudies-arrayexpress

TIGIT+ Tregs

Project description:TIGIT+ Tregs suppress Th1 and Th17 responses while sparing Th2 responses. Analysis of global gene expression of TIGIT+ vs. TIGIT- Tregs from naive mice reveled that TIGIT+ Tregs display an activated phenotype and are enriched for Treg signature genes including the Treg effector molecule Fgl2 which enables them to selectively spare Th2 responses. TIGIT+ and TIGIT- Tregs were sorted from naïve Foxp3-GFP KI mice (pooled spleen and lymph nodes) TIGIT: T cell immunoreceptor with Ig and ITIM domains

2014-12-12 | E-GEOD-56299 | biostudies-arrayexpress

Role of Adenosine 2A Receptors (A2AR) on regulatory T cells (Tregs)

Project description:The adenosine 2A receptor (A2AR) is expressed on regulatory T cells (Tregs), but the functional significance is currently unknown. We compared the gene expression between wild-type (WT) and A2AR knockout (KO) Tregs and between WT Tregs treated with vehicle or a selective A2AR agonist. FACS-sorted GFP positive Tregs from WT or A2AR KO FoxP3GFP mouse spleen and lymph nodes were incubated 18 hr with vehicle (DMSO), a separate set of WT Tregs were incubated with the selective A2AR agonist ATL1222 10 nM (Dogwood Pharmaceuticals, Inc.) for 18 hr prior to RNA isolation.

2012-05-31 | E-GEOD-34006 | biostudies-arrayexpress

Transcriptome analysis of TLR2-activated Th17 cells

Project description:Naïve CD4, Th17 (TGFB+IL6), Th17 (TGFb+IL6) + PAM3CSK4, and Th17 (TGFB+IL6) + biglycan samples were sequenced after 3d differentiation

2021-05-15 | GSE174469 | GEO

Compare gene expression profiles of TCR transgenic CD4+ T helper type 1 (Th1) vs. type 17 (Th17) cells optimally stimulated by antigen and differentiated under Th1 or Th17 conditions.

Project description:The comparison of Th1 vs. Th17 cell expression profile has been plagued by 1) rarely use of physiologically relevant antigen-driven T helper cell differentiation; and 2) cell lineage tracking system to enrich highly pure Th subsets. We began our attempt to produce large numbers of antigen-specific T helper subsets for expression profiling, when Foxp3GFP knockin mice were first made by our laboratory in 2005. We crossed this line with syngeneic TEa TCR transgenic mice in C57BL/6 background, and use FACS to sort optimally stimulated, highly pure GFP(Foxp3)-negative populations for Th1 vs. Th17 expression profile comparison.

2019-03-15 | E-MTAB-7661 | biostudies-arrayexpress

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