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Dynamic changes of nonepithelial thymic stroma during thymus organogenesis

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE163520 | GEO | 2022/05/13

REPOSITORIES: GEO

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microRNA expression in thymic epithelial cells

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.

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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.

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