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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE67961 | GEO | 2015/04/29

SECONDARY ACCESSION(S): PRJNA281376

REPOSITORIES: GEO

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The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells.

Project description:The balance between Th17 and T regulatory (Treg) cells critically modulates immune homeostasis, with an inadequate Treg response contributing to inflammatory disease. Using an unbiased chemical biology approach, we identified a novel role for the dual specificity tyrosine-phosphorylation-regulated kinase DYRK1A in regulating this balance. Inhibition of DYRK1A enhances Treg differentiation and impairs Th17 differentiation without affecting known pathways of Treg/Th17 differentiation. Thus, DYRK1A represents a novel mechanistic node at the branch point between commitment to either Treg or Th17 lineages. Importantly, both Treg cells generated using the DYRK1A inhibitor harmine and direct administration of harmine itself potently attenuate inflammation in multiple experimental models of systemic autoimmunity and mucosal inflammation. Our results identify DYRK1A as a physiologically relevant regulator of Treg cell differentiation and suggest a broader role for other DYRK family members in immune homeostasis. These results are discussed in the context of human diseases associated with dysregulated DYRK activity.

| S-EPMC4441007 | biostudies-literature

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. 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.

2015-04-29 | E-GEOD-64247 | biostudies-arrayexpress

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

2015-04-29 | GSE64247 | GEO

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

2015-04-29 | GSE67960 | GEO

Reconstruction of the dynamic regulatory network that controls Th17 cell differentiation by systematic perturbation in primary cells

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-03-07 | E-GEOD-43970 | biostudies-arrayexpress

UCP3 reciprocally controls CD4+ Th17 and Treg cell differentiation.

Project description:Uncoupling proteins (UCPs) are members of the mitochondrial anion carrier superfamily that can mediate the transfer of protons into the mitochondrial matrix from the intermembrane space. We have previously reported UCP3 expression in thymocytes, mitochondria of total splenocytes and splenic lymphocytes. Here, we demonstrate that Ucp3 is expressed in peripheral naive CD4+ T cells at the mRNA level before being markedly downregulated following activation. Non-polarized, activated T cells (Th0 cells) from Ucp3-/- mice produced significantly more IL-2, had increased expression of CD25 and CD69 and were more proliferative than Ucp3+/+ Th0 cells. The altered IL-2 expression observed between T cells from Ucp3+/+ and Ucp3-/- mice may be a factor in determining differentiation into Th17 or induced regulatory (iTreg) cells. When compared to Ucp3+/+, CD4+ T cells from Ucp3-/- mice had increased FoxP3 expression under iTreg conditions. Conversely, Ucp3-/- CD4+ T cells produced a significantly lower concentration of IL-17A under Th17 cell-inducing conditions in vitro. These effects were mirrored in antigen-specific T cells from mice immunized with KLH and CT. Interestingly, the altered responses of Ucp3-/- T cells were partially reversed upon neutralisation of IL-2. Together, these data indicate that UCP3 acts to restrict the activation of naive T cells, acting as a rheostat to dampen signals following TCR and CD28 co-receptor ligation, thereby limiting early activation responses. The observation that Ucp3 ablation alters the Th17:Treg cell balance in vivo as well as in vitro suggests that UCP3 is a potential target for the treatment of Th17 cell-mediated autoimmune diseases.

| S-EPMC7676685 | biostudies-literature

RORA proximal enhancer regulates its expression during early human Th17 cell differentiation

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

2024-05-23 | GSE243064 | GEO

Kinase-independent activity of DYRK1A promotes viral entry of highly pathogenic human coronaviruses

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

2023-04-02 | GSE213999 | GEO

Orchestrated intron retention regulates normal granulocyte differentiation

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-06-27 | E-GEOD-48307 | biostudies-arrayexpress

Protein kinase inhibitor ? reciprocally regulates osteoblast and adipocyte differentiation by downregulating leukemia inhibitory factor.

Project description:The protein kinase inhibitor (Pki) gene family inactivates nuclear protein kinase A (PKA) and terminates PKA-induced gene expression. We previously showed that Pkig is the primary family member expressed in osteoblasts and that Pkig knockdown increases the effects of parathyroid hormone and isoproterenol on PKA activation, gene expression, and inhibition of apoptosis. Here, we determined whether endogenous levels of Pkig regulate osteoblast differentiation. Pkig is the primary family member in murine embryonic fibroblasts (MEFs), murine marrow-derived mesenchymal stem cells, and human mesenchymal stem cells. Pkig deletion increased forskolin-dependent nuclear PKA activation and gene expression and Pkig deletion or knockdown increased osteoblast differentiation. PKA signaling is known to stimulate adipogenesis; however, adipogenesis and osteogenesis are often reciprocally regulated. We found that the reciprocal regulation predominates over the direct effects of PKA since adipogenesis was decreased by Pkig deletion or knockdown. Pkig deletion or knockdown also simultaneously increased osteogenesis and decreased adipogenesis in mixed osteogenic/adipogenic medium. Pkig deletion increased PKA-induced expression of leukemia inhibitory factor (Lif) mRNA and LIF protein. LIF neutralizing antibodies inhibited the effects on osteogenesis and adipogenesis of either Pkig deletion in MEFs or PKI? knockdown in both murine and human mesenchymal stem cells. Collectively, our results show that endogenous levels of Pkig reciprocally regulate osteoblast and adipocyte differentiation and that this reciprocal regulation is mediated in part by LIF. Stem Cells 2013;31:2789-2799.

| S-EPMC3930625 | biostudies-literature

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