Dataset Information

IRF7-dependent IFN-? production in response to RANKL promotes medullary thymic epithelial cell development.

ABSTRACT: The contributions of IFN regulatory factor (IRF) 3/7 and the type I IFNs IFN-?/? to the innate host defense have been extensively investigated; however, their role in thymic development is less clear. In this study, we show that mice lacking the type I IFN receptor IFN-?/? receptor (IFNAR) or the downstream transcription factor STAT1 harbor a significant reduction in self-Ag-presenting, autoimmune regulator (AIRE)(+) medullary thymic epithelial cells (mTECs). Constitutive IFNAR signaling occurs in the thymic medulla in the absence of infection or inflammation. Receptor activator for NF-?B (RANK) ligand stimulation results in IFN-? upregulation, which in turn inhibits RANK signaling and facilitates AIRE expression in mTECs. Finally, we find that IRF7 is required for thymic IFN-? induction, maintenance of thymic architecture, and mTEC differentiation. We conclude that spatially and temporally coordinated cross talks between the RANK ligand/RANK and IRF7/IFN-?/IFNAR/STAT1 pathways are essential for differentiation of AIRE(+) mTECs.

SUBMITTER: Otero DC

PROVIDER: S-EPMC3608802 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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IRF7-dependent IFN-β production in response to RANKL promotes medullary thymic epithelial cell development.

Otero Dennis C DC Baker Darren P DP David Michael M

Journal of immunology (Baltimore, Md. : 1950) 20130225 7

The contributions of IFN regulatory factor (IRF) 3/7 and the type I IFNs IFN-α/β to the innate host defense have been extensively investigated; however, their role in thymic development is less clear. In this study, we show that mice lacking the type I IFN receptor IFN-α/β receptor (IFNAR) or the downstream transcription factor STAT1 harbor a significant reduction in self-Ag-presenting, autoimmune regulator (AIRE)(+) medullary thymic epithelial cells (mTECs). Constitutive IFNAR signaling occurs ...[more]

PMID: 23440417

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Project description:BackgroundMedullary thymic epithelial cells (mTECs) are characterized by ectopic expression of self-antigens during the establishment of central tolerance. The autoimmune regulator (Aire), which is specifically expressed in mTECs, is responsible for the expression of a large repertoire of tissue-restricted antigens (TRAs) and plays a role in the development of mTECs. However, Aire-deficient mTECs still express TRAs. Moreover, a subset of mTECs, which are considered to be at a stage of terminal differentiation, exists in the Aire-deficient thymus. The phenotype of a specific cell type in a multicellular organism is governed by the epigenetic regulation system. DNA methylation modification is an important component of this system. Every cell or tissue type displays a DNA methylation profile, consisting of tissue-dependent and differentially methylated regions (T-DMRs), and this profile is involved in cell-type-specific genome usage. The aim of this study was to examine the DNA methylation profile of mTECs by using Aire-deficient mTECs as a model.ResultsWe identified the T-DMRs of mTECs (mTEC-T-DMRs) via genome-wide DNA methylation analysis of Aire(-/-) mTECs by comparison with the liver, brain, thymus, and embryonic stem cells. The hypomethylated mTEC-T-DMRs in Aire(-/-) mTECs were associated with mTEC-specific genes, including Aire, CD80, and Trp63, as well as other genes involved in the RANK signaling pathway. While these mTEC-T-DMRs were also hypomethylated in Aire(+/+) mTECs, they were hypermethylated in control thymic stromal cells. We compared the pattern of DNA methylation levels at a total of 55 mTEC-T-DMRs and adjacent regions and found that the DNA methylation status was similar for Aire(+/+) and Aire(-/-) mTECs but distinct from that of athymic cells and tissues.ConclusionsThese results indicate a unique DNA methylation profile that is independent of Aire in mTECs. This profile is distinct from other cell types in the thymic microenvironment and is indicated to be involved in the differentiation of the mTEC lineage.

Dataset Information

IRF7-dependent IFN-? production in response to RANKL promotes medullary thymic epithelial cell development.

Publications

IRF7-dependent IFN-β production in response to RANKL promotes medullary thymic epithelial cell development.

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