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Critical role of Jmjd3 in the maintenance and function of the thymic medulla for immunological tolerance

ABSTRACT: Critical role of Jmjd3 in the maintenance and function of the thymic medulla for immunological tolerance

PROVIDER: PRJNA433875 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6691650.fastq.gz	Fastqsanger.gz
	SRR6691670.fastq.gz	Fastqsanger.gz
	SRR6691651.fastq.gz	Fastqsanger.gz
	SRR6691671.fastq.gz	Fastqsanger.gz
	SRR6691652.fastq.gz	Fastqsanger.gz

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Critical role of Jmjd3 in the maintenance and function of the thymic medulla for immunological tolerance

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

2021-02-08 | GSE110503 | GEO

Jmjd3 is required for tissue-restricted antigens expression in mTECs

Project description:To understand the role of Jmjd3 in medullary thymic epithelial cells (mTECs) function and development, Jmjd3 was conditionally deleted in thymic epithelial cells. At the age of 4 weeks, mTECs were sorted by flow cytometry and RNA-seq was performed to identify the genes targeted by Jmjd3 for repression.

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Aire suppresses CTLA-4 expression from thymic stroma to control autoimmunity

Project description:We show that thymic epithelial cells in the medulla (mTECs) that present self-antigens (self-Ags) to developing thymocytes for establishing immunological self-tolerance also express CTLA-4 if Aire, loss of which is responsible for the hereditary autoimmunity, is nonfunctional. Upon binding with its ligand, CD80 and CD86, expressed on thymic DCs, CTLA-4/ligand complex was internalized by Aire-deficient mTECs. This attenuated the ability of DCs to provide costimulatory signals and to present self-Ags, resulting in the reduced production of Tregs.

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Project description:We have compared the transcriptional profiles from two epithelial cell types to find genes specifically expressed in thymic medullary epithelial cells. Epithelial cells from thyroid and thymic medulla from C57BL/6 mice were sorted and their transcriptional profiles compared. Cells were gated as viable, Epcam+ CD45- for thyroid and viable, Epcam+ CD45- UEA+ for thymic medulla.

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Project description:Autoimmune regulator (Aire) is a unique transcriptional regulator that induces promiscuous expression of thousands of tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs), a step critical for induction of immunological self-tolerance. Although several recent studies provided very important molecular insights into how Aire operates, a more comprehensive understanding of this process still remains elusive. Here we demonstrate that a lysine deacetylase Sirtuin-1 (Sirt1) is predominantly expressed in mature Aire+ mTECs, where it is required for expression of Aire-dependent TRA genes and a subsequent induction of immunological self-tolerance. Our study elucidates a previously unknown molecular mechanism for Aire-mediated transcriptional regulation and uncovers a unique functional role for Sirt1 in preventing organ-specific autoimmunity. ~100ng of total RNA isolated by Trizol extraction from MHC-II low and high mTECs (pool of 3 mice) was used to generate poly-A-selected transcriptome libraries using the non-directionnal TruSeq V3 RNA Sample Prep Kit (without additional pre-amplification) following the manufacturer's protocols. Enrichment of DNA fragment with adapter molecules on both ends was done using 15 cycles of PCR amplification using the Illumina PCR mix and primer cocktail. Paired-end (2 × 100 bp) sequencing was performed using the Illumina HiSeq2000 machine.

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Sirt1 is essential for Aire-mediated induction of central immunological tolerance

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