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FoxP3-mediated blockage of ryanodine receptor 2 is the molecular basis for the contact-based suppression by regulatory T cells

ABSTRACT: The suppression mechanism of regulatory T cells (Tregs) is an intensely investigated topic. As our focus has shifted towards a model centered on indirect inhibition of dendritic cells, a universally applicable effector mechanism controlled by the transcription factor forkhead box P3 (FoxP3) expression has not been found. Here, we report that FoxP3 blocks the transcription of ER Ca2+-release channel ryanodine receptor 2 (RyR2). Reduced RyR2 shuts down basal Ca2+ oscillation in Tregs, which reduces m-Calpain activities that is needed for T cells to disengage from DCs, suggesting a persistent blockage of DC antigen presentation. RyR2 deficiency renders the CD4+ T cell pool to become immune suppressive, and behave in the same manner as FoxP3+ Tregs in viral infection, asthma, hypersensitivity, colitis and tumor development. In the absence of FoxP3, RyR2-deficient CD4+ T cells (CKO) rescue the systemic autoimmunity associated with Scurfy mice. Therefore, FoxP3-mediated Ca2+ signaling inhibition may be a central effector mechanism of Treg immune suppression.

ORGANISM(S): Mus musculus

PROVIDER: GSE237032 | GEO | 2023/12/20

REPOSITORIES: GEO

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Enhancing calmodulin binding to cardiac ryanodine receptor completely inhibits pressure-overload induced hypertrophic signaling

Project description:Purpose: Cardiac hypertrophy is a well-known major risk factor for poor prognosis in patients with cardiovascular diseases. Dysregulation of intracellular Ca2+ is involved in the pathogenesis of cardiac hypertrophy. However, the precise mechanism underlying cardiac hypertrophy remains elusive. Here, we investigated whether pressure-overload induced hypertrophy can be induced by destabilization of cardiac ryanodine receptor (RyR2) through calmodulin (CaM) dissociation and subsequent Ca2+ leakage, and whether it can be genetically rescued by enhancing the binding affinity of CaM to RyR2. Methods: To examine the role of CaM-RyR2 complex in the development of pressure-overload induced cardiac hypertrophy, whole transcriptome analysis using RNA-seq analysis in the hearts from WT and homozygous RyR2V3599K/V3599K (V3599K) mice with or without transverse aortic constriction (TAC) was performed to elucidate the RyR2 signaling pathway in the heart. Results: Gene expression increased in WT (+TAC) hearts compared to WT (-TAC) hearts; however, this increase was not observed in V3599K (+TAC) hearts. Conclusions: Enhanced CaM binding to RyR2 decreased expression of hypertrophy-related genes.

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Transcription profiling of regulatory T cells (Treg) and Effector CD4+ T cells in healthy B6 mice and sick mice with scurfy mutation - Foxp3-deficient Treg cells do not revert into conventional Effector CD4+ T cells but constitute a unique cell subset

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2009-09-04 | E-GEOD-11775 | biostudies-arrayexpress

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2018-05-18 | PXD005477 | Pride

Quantitative Proteomics Reveals Specialized Wiring of Signaling Pathways that Protects Human Regulatory T Cell Identity - 6 populations ex vivo

2018-05-18 | PXD007744 | Pride

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2023-08-30 | PXD042295 | Pride

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Comparison of expression profiles of Foxp3(+)epigenetics(-) T cells, Foxp3(-)epigenetics(+) T cells, and Foxp3(+)epigenetics(+) T cells

Project description:Analysis of Foxp3(+)epigenetics(-) T cells, Foxp3(-)epigenetics(+) T cells, and Foxp3(+)epigenetics(+) T cells. Results indicate regulatory T cell (Treg) ontogenesis requires two independent processes, expression of the transcription factor Foxp3 and establishment of Treg epigenetic programs induced by T cell receptor (TCR) stimulation. GFP+CD4+ and GFP-CD4+ splenocytes were sorted from DEREG and DEREG/Scurfy mice. These cells were activated with anti-CD3/CD28 antibodies, and then transduced with Foxp3-expressing retrovirus (pGCSamIN, NGFR marker). NGFR+ T cells sorted were subjected to microarray analysis (Affymetrix, mouse genome 430 2.0 array). To normalize the experimental conditions, Tregs (GFP+ T cells from DEREG) and Tconv (GFP- T cells from DEREG) were also activated and transduced with empty vector. Two replicates each.

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Effect of high-dose cyclophosphamide gene expression profiles in cardiomyocytes of C57BL/6J mice

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2022-01-21 | GSE194073 | GEO

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