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A novel method to identify Post-Aire stages of medullary thymic epithelial cell differentiation.

ABSTRACT: Autoimmune regulator⁺ (Aire) medullary thymic epithelial cells (mTECs) play a critical role in tolerance induction. Several studies demonstrated that Aire⁺ mTECs differentiate further into Post-Aire cells. Yet, the identification of terminal stages of mTEC maturation depends on unique fate-mapping mouse models. Herein, we resolve this limitation by segmenting the mTEC^hi (MHCII^hi CD80^hi ) compartment into mTEC^A/hi (CD24^- Sca1^- ), mTEC^B/hi (CD24⁺ Sca1^- ), and mTEC^C/hi (CD24⁺ Sca1⁺ ). While mTEC^A/hi included mostly Aire-expressing cells, mTEC^B/hi contained Aire⁺ and Aire^- cells and mTEC^C/hi were mainly composed of cells lacking Aire. The differential expression pattern of Aire led us to investigate the precursor-product relationship between these subsets. Strikingly, transcriptomic analysis of mTEC^A/hi , mTEC^B/hi , and mTEC^C/hi sequentially mirrored the specific genetic program of Early-, Late- and Post-Aire mTECs. Corroborating their Post-Aire nature, mTEC^C/hi downregulated the expression of tissue-restricted antigens, acquired traits of differentiated keratinocytes, and were absent in Aire-deficient mice. Collectively, our findings reveal a new and simple blueprint to survey late stages of mTEC differentiation.

SUBMITTER: Ferreirinha P

PROVIDER: S-EPMC7891440 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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A novel method to identify Post-Aire stages of medullary thymic epithelial cell differentiation.

Ferreirinha Pedro P Ribeiro Camila C Morimoto Junko J Landry Jonathan J M JJM Matsumoto Minoru M Meireles Catarina C White Andrea J AJ Ohigashi Izumi I Araújo Leonor L Benes Vladimir V Takahama Yousuke Y Anderson Graham G Matsumoto Mitsuru M Alves Nuno L NL

European journal of immunology 20200915 2

Autoimmune regulator+ (Aire) medullary thymic epithelial cells (mTECs) play a critical role in tolerance induction. Several studies demonstrated that Aire+ mTECs differentiate further into Post-Aire cells. Yet, the identification of terminal stages of mTEC maturation depends on unique fate-mapping mouse models. Herein, we resolve this limitation by segmenting the mTEChi (MHCIIhi CD80hi ) compartment into mTECA/hi (CD24- ...[more]

PMID: 32845012

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Project description:BACKGROUND: Medullary 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. RESULTS: We 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. CONCLUSIONS: These 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

A novel method to identify Post-Aire stages of medullary thymic epithelial cell differentiation.

Publications

A novel method to identify Post-Aire stages of medullary thymic epithelial cell differentiation.

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