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Rank signaling links the development of invariant ?? T cell progenitors and Aire(+) medullary epithelium.

ABSTRACT: The thymic medulla provides a specialized microenvironment for the negative selection of T cells, with the presence of autoimmune regulator (Aire)-expressing medullary thymic epithelial cells (mTECs) during the embryonic-neonatal period being both necessary and sufficient to establish long-lasting tolerance. Here we showed that emergence of the first cohorts of Aire(+) mTECs at this key developmental stage, prior to ?? T cell repertoire selection, was jointly directed by Rankl(+) lymphoid tissue inducer cells and invariant V?5(+) dendritic epidermal T cell (DETC) progenitors that are the first thymocytes to express the products of gene rearrangement. In turn, generation of Aire(+) mTECs then fostered Skint-1-dependent, but Aire-independent, DETC progenitor maturation and the emergence of an invariant DETC repertoire. Hence, our data attributed a functional importance to the temporal development of V?5(+) ?? T cells during thymus medulla formation for ?? T cell tolerance induction and demonstrated a Rank-mediated reciprocal link between DETC and Aire(+) mTEC maturation.

SUBMITTER: Roberts NA

PROVIDER: S-EPMC3368267 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Rank signaling links the development of invariant γδ T cell progenitors and Aire(+) medullary epithelium.

Roberts Natalie A NA White Andrea J AJ Jenkinson William E WE Turchinovich Gleb G Nakamura Kyoko K Withers David R DR McConnell Fiona M FM Desanti Guillaume E GE Benezech Cecile C Parnell Sonia M SM Cunningham Adam F AF Paolino Magdalena M Penninger Josef M JM Simon Anna Katharina AK Nitta Takeshi T Ohigashi Izumi I Takahama Yousuke Y Caamano Jorge H JH Hayday Adrian C AC Lane Peter J L PJ Jenkinson Eric J EJ Anderson Graham G

Immunity 20120315 3

The thymic medulla provides a specialized microenvironment for the negative selection of T cells, with the presence of autoimmune regulator (Aire)-expressing medullary thymic epithelial cells (mTECs) during the embryonic-neonatal period being both necessary and sufficient to establish long-lasting tolerance. Here we showed that emergence of the first cohorts of Aire(+) mTECs at this key developmental stage, prior to αβ T cell repertoire selection, was jointly directed by Rankl(+) lymphoid tissue ...[more]

PMID: 22425250

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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

Rank signaling links the development of invariant ?? T cell progenitors and Aire(+) medullary epithelium.

Publications

Rank signaling links the development of invariant γδ T cell progenitors and Aire(+) medullary epithelium.

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