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Epithelial LT?R signaling controls the population size of the progenitors of medullary thymic epithelial cells in neonatal mice.

ABSTRACT: The establishment of T cell central tolerance critically relies on the development and maintenance of the medullary thymic epithelial cells (mTECs). Disrupted signaling of lymphotoxin beta receptor (LT?R) results in dramatically reduced mTEC population. However, whether LT?R directly or indirectly control mTECs remains undetermined; how LT?R controls this process also remain unclear. In this study, by utilizing K14-Cre?×?Ltbr^fl/fl conditional knockout (cKO) mice, we show that epithelial intrinsic LT?R was essential for the mTEC development postnatally. Mechanistically, LT?R did not directly impact the proliferation or survival of mTECs; the maturation of mTECs from MHC-II^lo to MHC-II^hi stage was also unaltered in the absence of LT?R; interestingly, the number of mTEC progenitors (Cld3,4^hiSSEA-1⁺) was found significantly reduced in LT?R cKO mice at the neonatal stage, but not at E18.5. Consequently, epithelial deficiency of LT?R resulted in significant defect of thymic negative selection as demonstrated using OT-I and RIP-OVA transgenic mouse system. In summary, our study clarifies the epithelial intrinsic role of LT?R on mTEC development and function; more importantly, it reveals a previously unrecognized function of LT?R on the control of the size of mTEC progenitor population.

SUBMITTER: Wu W

PROVIDER: S-EPMC5349570 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Epithelial LTβR signaling controls the population size of the progenitors of medullary thymic epithelial cells in neonatal mice.

Wu Weiwei W Shi Yaoyao Y Xia Huan H Chai Qian Q Jin Caiwei C Ren Boyang B Zhu Mingzhao M

Scientific reports 20170314

The establishment of T cell central tolerance critically relies on the development and maintenance of the medullary thymic epithelial cells (mTECs). Disrupted signaling of lymphotoxin beta receptor (LTβR) results in dramatically reduced mTEC population. However, whether LTβR directly or indirectly control mTECs remains undetermined; how LTβR controls this process also remain unclear. In this study, by utilizing K14-Cre × Ltbr<sup>fl/fl</sup> conditional knockout (cKO) mice, we show that epitheli ...[more]

PMID: 28290551

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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

Epithelial LT?R signaling controls the population size of the progenitors of medullary thymic epithelial cells in neonatal mice.

Publications

Epithelial LTβR signaling controls the population size of the progenitors of medullary thymic epithelial cells in neonatal mice.

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