Inborn errors of thymic stromal cell development and function

Kreins, Alexandra; Maio, Stefano; Dhalla, Fatima

doi:10.1007/s00281-020-00826-9

Cited by 20 publications

(26 citation statements)

References 154 publications

(289 reference statements)

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“…Differentiation of thymic epithelial cells (TECs) is dependent on the Foxn1 transcription factor 28 – 35 , and defects in epithelial specification and development are known to block T cell development, resulting in profound immunodeficiency and/or autoimmunity 36 , 37 . Because the thymic epithelium occupies such a central role in the formation and maintenance of cellular immunity, it has become an attractive target for immunomodulatory and regenerative therapies 38 – 43 designed to correct congenital lack or iatrogenic loss of thymic tissue or to modify failing central tolerance.…”

Section: Mainmentioning

confidence: 99%

Developmental dynamics of two bipotent thymic epithelial progenitor types

Nusser

Sagar

Swann

et al. 2022

Nature

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T cell development in the thymus is essential for cellular immunity and depends on the organotypic thymic epithelial microenvironment. In comparison with other organs, the size and cellular composition of the thymus are unusually dynamic, as exemplified by rapid growth and high T cell output during early stages of development, followed by a gradual loss of functional thymic epithelial cells and diminished naive T cell production with age1–10. Single-cell RNA sequencing (scRNA-seq) has uncovered an unexpected heterogeneity of cell types in the thymic epithelium of young and aged adult mice11–18; however, the identities and developmental dynamics of putative pre- and postnatal epithelial progenitors have remained unresolved1,12,16,17,19–27. Here we combine scRNA-seq and a new CRISPR–Cas9-based cellular barcoding system in mice to determine qualitative and quantitative changes in the thymic epithelium over time. This dual approach enabled us to identify two principal progenitor populations: an early bipotent progenitor type biased towards cortical epithelium and a postnatal bipotent progenitor population biased towards medullary epithelium. We further demonstrate that continuous autocrine provision of Fgf7 leads to sustained expansion of thymic microenvironments without exhausting the epithelial progenitor pools, suggesting a strategy to modulate the extent of thymopoietic activity.

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Section: Mainmentioning

confidence: 99%

Developmental dynamics of two bipotent thymic epithelial progenitor types

Nusser

Sagar

Swann

et al. 2022

Nature

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“…The thymus is an essential organ for the development of mammalian T cells. 14 It is composed of thymocytes and thymic stromal cells. Thymus stromal cells include thymus epithelial cells, fibroblasts, mesenchymal cells, pericytes and endothelial cells.…”

Section: Thymus and Thymic Epithelial Cellsmentioning

confidence: 99%

“…The thymus is an essential organ for the development of mammalian T cells 14 . It is composed of thymocytes and thymic stromal cells.…”

Section: Thymus and Thymic Epithelial Cellsmentioning

confidence: 99%

Regulation of thymic T regulatory cell differentiation by TECs in health and disease

2021

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The thymus produces self-limiting and self-tolerant T cells through the interaction between thymocytes and thymus epithelial cells (TECs), thereby generating central immune tolerance. The TECs are composed of cortical and medullary thymic epithelial cells, which regulate the positive and negative selection of T cells, respectively.How to cite this article: Tao Z, Jiang Y, Xia S. Regulation of thymic T regulatory cell differentiation by TECs in health and disease.

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“…Due to their central role in thymic function, deficiencies affecting the development TECs or resulting in insufficient cues for their proliferation or maintenance from other thymic cells, result in qualitative or quantitative thymic dysfunction ( 12 ).…”

Section: Introductionmentioning

confidence: 99%

Novel Combination of Surface Markers for the Reliable and Comprehensive Identification of Human Thymic Epithelial Cells by Flow Cytometry: Quantitation and Transcriptional Characterization of Thymic Stroma in a Pediatric Cohort

et al. 2021

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Thymic epithelial cells (TECs) are essential in supporting the development of mature T cells from hematopoietic progenitor cells and facilitate their lineage-commitment, proliferation, T-cell receptor repertoire selection and maturation. While animal model systems have greatly aided in elucidating the contribution of stromal cells to these intricate processes, human tissue has been more difficult to study, partly due to a lack of suitable surface markers comprehensively defining human TECs. Here, we conducted a flow cytometry based surface marker screen to reliably identify and quantify human TECs and delineate medullary from cortical subsets. These findings were validated by transcriptomic and histologic means. The combination of EpCAM, podoplanin (pdpn), CD49f and CD200 comprehensively identified human TECs and not only allowed their reliable distinction in medullary and cortical subsets but also their detailed quantitation. Transcriptomic profiling of each subset in comparison to fibroblasts and endothelial cells confirmed the identity of the different stromal cell subsets sorted according to the proposed strategy. Our dataset not only demonstrated transcriptional similarities between TEC and cells of mesenchymal origin but furthermore revealed a subset-specific distribution of a specific set of extracellular matrix-related genes in TECs. This indicates that TECs significantly contribute to the distinct compartmentalization – and thus function – of the human thymus. We applied the strategy to quantify TEC subsets in 31 immunologically healthy children, which revealed sex-specific differences of TEC composition early in life. As the distribution of mature CD4- or CD8-single-positive thymocytes was correspondingly altered, the composition of the thymic epithelial compartment may directly impact on the CD4-CD8-lineage choice of thymocytes. We prove that the plain, reliable strategy proposed here to comprehensively identify human TEC subpopulations by flow cytometry based on surface marker expression is suitable to determine their frequency and phenotype in health and disease and allows sorting of live cells for downstream analysis. Its use reaches from a reliable diagnostic tool for thymic biopsies to improved phenotypic characterization of thymic grafts intended for therapeutic use.

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Inborn errors of thymic stromal cell development and function

Cited by 20 publications

References 154 publications

Developmental dynamics of two bipotent thymic epithelial progenitor types

Developmental dynamics of two bipotent thymic epithelial progenitor types

Regulation of thymic T regulatory cell differentiation by TECs in health and disease

Novel Combination of Surface Markers for the Reliable and Comprehensive Identification of Human Thymic Epithelial Cells by Flow Cytometry: Quantitation and Transcriptional Characterization of Thymic Stroma in a Pediatric Cohort

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