Indispensable epigenetic control of thymic epithelial cell development and function by Polycomb Repressive Complex 2
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE112050 | GEO | 2021/02/19
REPOSITORIES: GEO
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Project description:Thymic epithelial cells (TEC) guide selection of a T-cell repertoire that is reactive to pathogens but tolerant to self. While this process is known to involve the promiscuous expression of virtually the entire protein-coding gene repertoire by TEC, the extent to which these cells reproduce peripheral isoform structures is unknown. We performed a transcriptomic investigation of transcript structures and splicing factor expression in medullary TEC and 21 peripheral tissues. Our results indicate that TEC re-use a small number of peripheral splicing factors to recreate a limited subset of the peripheral splice isoform repertoire. We found, for example, that TEC lacked both neuronal microexons and the splicing factor, Srrm4, which promotes their inclusion. We demonstrate a functional role for the Rbfox splicing factors in promoting medullary TEC development and the alternative splicing of promiscuously expressed genes. Our findings have implications for understanding autoimmune diseases and the development of antigen-specific immunotherapies.
2021-08-03 | GSE145914 | GEO
Project description:Thymic epithelial cells (TEC) guide selection of a T-cell repertoire that is reactive to pathogens but tolerant to self. While this process is known to involve the promiscuous expression of virtually the entire protein-coding gene repertoire by TEC, the extent to which these cells reproduce peripheral isoform structures is unknown. We performed a transcriptomic investigation of transcript structures and splicing factor expression in medullary TEC and 21 peripheral tissues. Our results indicate that TEC re-use a small number of peripheral splicing factors to recreate a limited subset of the peripheral splice isoform repertoire. We found, for example, that TEC lacked both neuronal microexons and the splicing factor, Srrm4, which promotes their inclusion. We demonstrate a functional role for the Rbfox splicing factors in promoting medullary TEC development and the alternative splicing of promiscuously expressed genes. Our findings have implications for understanding autoimmune diseases and the development of antigen-specific immunotherapies.
2021-08-03 | GSE145913 | GEO
Project description:Thymic epithelial cells (TEC) guide selection of a T-cell repertoire that is reactive to pathogens but tolerant to self. While this process is known to involve the promiscuous expression of virtually the entire protein-coding gene repertoire by TEC, the extent to which these cells reproduce peripheral isoform structures is unknown. We performed a transcriptomic investigation of transcript structures and splicing factor expression in medullary TEC and 21 peripheral tissues. Our results indicate that TEC re-use a small number of peripheral splicing factors to recreate a limited subset of the peripheral splice isoform repertoire. We found, for example, that TEC lacked both neuronal microexons and the splicing factor, Srrm4, which promotes their inclusion. We demonstrate a functional role for the Rbfox splicing factors in promoting medullary TEC development and the alternative splicing of promiscuously expressed genes. Our findings have implications for understanding autoimmune diseases and the development of antigen-specific immunotherapies.
2021-08-03 | GSE145930 | GEO
Project description:The thymic stroma provides the microenvironment for T cell lineage commitment, development, maturation, and repertoire selection. While the thymic epithelial cell (TEC) compartment is relatively well characterised, a comparably detailed analysis of the non-TEC stromal compartment including the endothelial cells and fibroblasts is currently lacking. Here, we probe the composition of thymic mesenchymal cells and their dynamic change during thymus organogenesis. Using a single cell transcriptomic approach, we identify previously unappreciated heterogeneity within the non-TEC stromal compartment and demonstrate dynamic shifts within non-TEC stromal cell populations over thymic development. We then use a compound heterozygous model (Tbx1+/-Crkl+/-) for 22q11.2DS syndrome to show that significant reductions of multiple mesenchymal subpopulations associated with functional defects and accelerated aging are associated with the thymic hypoplasia observed in this condition. Thus, we provided a comprehensive picture of non-TEC thymic stromal development and their functional defects in a disease model of thymic hypoplasia.
2022-05-13 | GSE163520 | GEO
Project description:Thymic epithelial cells (TEC) control T cell development and play essential roles in establishing self-tolerance. Transcription factors controlling TEC development are poorly characterized. We report that Klf6 plays a critical role in TEC development. Mice deficient for Klf6 in TEC had a hypoplastic thymus - evident from fetal stages into adulthood. Proliferation of TEC was not reduced, but a dramatic increase in the frequency of apoptotic TEC in fetal and adult thymus was observed. Among cortical TEC (cTEC), we found expansion of a previously unreported cTEC population expressing the transcription factor Sox10. Medullary TEC (mTEC) subsets were not equally impacted with Ccl21a+ mTEC I and Tuft-like mTEC IV being disproportionately affected. Consistent with these TEC defects, naïve conventional T cells and NKT cells were reduced in the spleen, and signs of autoimmunity were evident. Thus, Klf6 has a pro- survival role in TEC and is also required for differentiation of the mTEC I and mTEC IV populations of TEC in adult mice. In this work, we report that mice with Foxn1-Cre mediated ablation of Klf6 in TEC demonstrate thymic hypoplasia beginning from prenatal life and extending through adulthood. Guided by single-cell transcriptional profiling, we determined that loss of Klf6 increased programmed cell death of TEC in prenatal and adult mice. In adult mice, thymic Klf6 deficiency severely impacted the mTEC I and mTEC IV populations. In addition, Klf6 deficiency led to the expansion of a previously uncharacterized cTEC population expressing Sox10 that is present in wild-type mice at very low frequencies. We observed concordant reductions of the naïve αβ T cell and iNKT pools in the periphery of young adult mice. Furthermore, we detected T cell infiltration in salivary and lacrimal glands, indicating defects in T cell tolerance.
2023-10-12 | GSE220270 | GEO
Project description:Thymic epithelial cells (TEC) control T cell development and play essential roles in establishing self-tolerance. Transcription factors controlling TEC development are poorly characterized. We report that Klf6 plays a critical role in TEC development. Mice deficient for Klf6 in TEC had a hypoplastic thymus - evident from fetal stages into adulthood. Proliferation of TEC was not reduced, but a dramatic increase in the frequency of apoptotic TEC in fetal and adult thymus was observed. Among cortical TEC (cTEC), we found expansion of a previously unreported cTEC population expressing the transcription factor Sox10. Medullary TEC (mTEC) subsets were not equally impacted with Ccl21a+ mTEC I and Tuft-like mTEC IV being disproportionately affected. Consistent with these TEC defects, naïve conventional T cells and NKT cells were reduced in the spleen, and signs of autoimmunity were evident. Thus, Klf6 has a pro- survival role in TEC and is also required for differentiation of the mTEC I and mTEC IV populations of TEC in adult mice. In this work, we report that mice with Foxn1-Cre mediated ablation of Klf6 in TEC demonstrate thymic hypoplasia beginning from prenatal life and extending through adulthood. Guided by single-cell transcriptional profiling, we determined that loss of Klf6 increased programmed cell death of TEC in prenatal and adult mice. In adult mice, thymic Klf6 deficiency severely impacted the mTEC I and mTEC IV populations. In addition, Klf6 deficiency led to the expansion of a previously uncharacterized cTEC population expressing Sox10 that is present in wild-type mice at very low frequencies. We observed concordant reductions of the naïve αβ T cell and iNKT pools in the periphery of young adult mice. Furthermore, we detected T cell infiltration in salivary and lacrimal glands, indicating defects in T cell tolerance.
2023-10-12 | GSE221073 | GEO
Project description:The thymus shapes the T cell receptor repertoire, and is one of the first organs to rapidly age, with gross changes in cellularity and architecture. To resolve the nature of these changes we used SMART-Seq2 on FACS purified thymic epithelial cells (TEC) across the first year of mouse life. We sorted 4 TEC populations in each of 5 mice at each age (1 week, 4 weeks, 16 weeks, 32 weeks and 52 weeks old).
2020-09-14 | E-MTAB-8560 | biostudies-arrayexpress
Project description:The thymus is primarily responsible for generating naïve, self-tolerant T cells from hematopoietic precursors. Thymic epithelial cells (TECs) together with other stromal cells create a specialized microenvironment which orchestrates the major selection processes for T cell development. Thymic function progressively deteriorates as part of the aging process, with a dramatic loss in TECs and T cell production, and this ultimately constrains the host immune repertoire. We have previously demonstrated the role of sex steroids in thymic involution in male mice, with surgical castration of middle-aged (9-12 month) male mice resulting in thymus regeneration, peaking around day 28. We have also demonstrated phenotypic alterations in TEC subsets within one week following castration that may contribute to this transient thymus regeneration effect. In this study, we aimed to examine genetic alterations in TEC and non-TEC stromal cell subsets (predominantly fibroblasts and endothelial cells) during age-related thymic involution (5-6 week old young adults compared to 9-12 month middle aged); and genetic changes in TEC and non-TEC at several timepoints following castration, to identify factors that may be involved in thymus regeneration.
2019-06-06 | GSE132278 | GEO
Project description:Thymic epithelial cells (TECs) support T cell development in the thymus. Cortical thymic epithelial cells (cTECs) facilitate positive selection of developing thymocytes whereas medullary thymic epithelial cells (mTECs) facilitate the deletion of self-reactive thymocytes in order to prevent autoimmunity. The mTEC compartment is highly dynamic with continuous maturation and turnover, but the genetic regulation of these processes remains poorly understood. MicroRNAs (miRNAs) are important regulators of TEC genetic programs since miRNA-deficient TECs are severely defective. However, the individual miRNAs important for TEC maintenance and function and their mechanisms of action remain unknown. Here, we demonstrate that miR-205 is highly and preferentially expressed in mTECs during both thymic ontogeny and in the postnatal thymus. This distinct expression is suggestive of functional importance for TEC biology. Genetic ablation of miR-205 in TECs, however, neither revealed a role for miR-205 in TEC function during homeostatic conditions nor during recovery from thymic stress conditions. Thus, despite its distinct expression, miR-205 on its own is largely dispensable for mTEC biology. In order to identify miRNAs differentially expressed in mTECs, we purified cortical thymic epithelial cells (cTECs), mTECs and CD45+ cells as three distinct populations and prepared RNA for microarray analysis. Thymic subsets were FACS-purified from 4-week old NOD wildtype mice. Thymi from 10-12 female mice were pooled together for stromal cell isolation for a total of 3 CD45+, 2 cTEC and 3 mTEC biologic replicates.
2015-07-28 | E-GEOD-68674 | biostudies-arrayexpress
Project description:The thymus is a primary lymphoid organ necessary for optimal T cell development. Here we show that liver X receptors, which are a class of nuclear receptors and transcription factors with diverse functions in metabolism and immunity, critically contribute to thymic integrity and function. LXRαβ-deficient mice develop a fatty, rapidly-involuting thymus, and acquire a shrunken and prematurely senescent peripheral T cell repertoire. The functions of LXRαβ are cell specific and the resulting phenotypes mutually independent. Whereas macrophages require LXRαβ for reverse cholesterol transport and lipid removal, thymic epithelial cells (TEC) and thymocytes respectively utilize LXRαβ for self-renewal and negative selection. Consequently, TEC-derived LXRαβ protect against premature involution in homeostasis and orchestrate thymic regeneration following stress, while thymocyte-derived LXRαβ limit cell disposal during negative selection and confer heightened sensitivity to experimental autoimmune encephalomyelitis. These results identify three distinct but complementary mechanisms by which LXRαβ govern T lymphocyte education.
2020-01-29 | GSE144342 | GEO