Adult Thymus Contains FoxN1− Epithelial Stem Cells that Are Bipotent for Medullary and Cortical Thymic Epithelial Lineages

Ucar, Ahmet; Ucar, Olga; Klug, Paula; Matt, Sonja; Brunk, Fabian; Hofmann, Thomas G.; Kyewski, Bruno

doi:10.1016/j.immuni.2014.07.005

Cited by 83 publications

(120 citation statements)

References 44 publications

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“…2 stem cells, and second, they are unable to rebuild the thymus after prenatal intoxication of Foxn1 + TECs (38,39). These cells may originate from the incomplete separation of the parathyroid and the thymus (40), as has been proposed previously for the cervical thymus in a reciprocal manner (21).…”

Section: Foxn1mentioning

confidence: 84%

Foxn1 Protein Expression in the Developing, Aging, and Regenerating Thymus

Rodé

Martins

Küblbeck

et al. 2015

The Journal of Immunology

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The forkhead box N1 (Foxn1) protein is the key regulator of thymic epithelial cell (TEC) development, yet how Foxn1 functions remains largely unknown. All mature TECs arise from Foxn1-expressing progenitors/immature TECs and it is widely assumed that TECs as a whole are defined by Foxn1 expression. However, data on the Foxn1 protein are virtually lacking. In this study, we developed novel tools to visualize Foxn1 protein expression at single-cell resolution. We generated Foxn1 knock-in mice expressing a C-terminal hemagglutinin-tagged Foxn1 protein, and a cytometry-grade monoclonal anti-Foxn1 Ab. We evaluated Foxn1 expression patterns in TEC subsets and its dynamics during normal thymus development, aging, injury, and regeneration. Upon challenges, upregulation of Foxn1 was a common feature of thymus regeneration, but the timing of Foxn1 expression changed and the responding TEC subsets depended on the type of treatment. Whereas dexamethasone and recombinant human fibroblast growth factor 7 promoted expansion of Foxn1+Ly51+CD80− TECs, castration led to expansion of Foxn1+Ly51−CD80+ TECs. Collectively, Foxn1 expression is highly heterogeneous in the normal thymus, with large fractions of Foxn1low or Foxn1− TECs accumulating with age. Furthermore, Foxn1 expression is responsive to perturbations.

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Section: Foxn1mentioning

confidence: 84%

Foxn1 Protein Expression in the Developing, Aging, and Regenerating Thymus

Rodé

Martins

Küblbeck

et al. 2015

The Journal of Immunology

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“…It is assumed that both mTECs and cTECs develop from common bi-potent thymic epithelial progenitors (TEPs) (Rossi et al, 2006), which remain incompletely characterized, particularly in the adult thymus (Ucar et al, 2014; Wong et al, 2014). However, more recent studies have also suggested the existence of mTEC lineage-specific progenitors/stem cells in both embryonic (Sekai et al, 2014) and adult thymus (Ohigashi et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

HDAC3 Is a Master Regulator of mTEC Development

et al. 2016

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The thymus provides a unique microenvironment enabling development and selection of T lymphocytes. Medullary thymic epithelial cells (mTECs) play a pivotal role in this process by facilitating negative selection of self-reactive thymocytes and the generation of Foxp3+ regulatory T cells. Although studies highlighted the non-canonical NFκB pathway as the key regulator of mTEC development, comprehensive understanding of the molecular pathways regulating this process still remains incomplete. Here we demonstrate that the development of functionally competent mTECs is regulated by the histone deacetylase 3 (Hdac3). Although histone deacetylases are global transcriptional regulators this effect is highly specific only to Hdac3, as neither Hdac1 nor Hdac2 inactivation caused mTEC ablation. Interestingly, Hdac3 induces an mTEC-specific transcriptional program independently of the previously recognized RANK-NFκB signaling pathway. Thus, our findings uncover yet another layer of complexity of TEC lineage divergence and highlight Hdac3 as a major and specific molecular switch crucial for mTEC differentiation.

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“…Recent studies have identified this progenitor cell population using different methods (Fig. ) . One research group identified this progenitor cell line by identifying a rare cell population derived from adult mouse thymic stromal cells that formed thymospheres, a property of progenitor cells.…”

Section: New Insights Into Mtec Development and Turnovermentioning

confidence: 99%

Central tolerance to self revealed by the autoimmune regulator

Chan

Anderson

2015

Annals of the New York Academy of Sciences

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The autoimmune regulator (Aire) was initially identified as the gene causing multiorgan system autoimmunity in humans, and deletion of this gene in mice also resulted in organ-specific autoimmunity. Aire regulates the expression of tissue-specific antigens (TSAs) in medullary thymic epithelial cells (mTECs), which play a critical role in the negative selection of autoreactive T cells and the generation of regulatory T cells. More recently, the role of Aire in the development of mTECs have helped elucidate its ability to present the spectrum of TSAs needed to prevent autoimmunity. Molecular characterization of the functional domains of Aire have revealed multiple binding partners that assist Aire’s function in altering gene transcription and chromatin remodeling. These recent advances have further highlighted the importance of Aire in central tolerance.

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Adult Thymus Contains FoxN1− Epithelial Stem Cells that Are Bipotent for Medullary and Cortical Thymic Epithelial Lineages

Cited by 83 publications

References 44 publications

Foxn1 Protein Expression in the Developing, Aging, and Regenerating Thymus

Foxn1 Protein Expression in the Developing, Aging, and Regenerating Thymus

HDAC3 Is a Master Regulator of mTEC Development

Central tolerance to self revealed by the autoimmune regulator

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