Redefining thymus medulla specialization for central tolerance

Cosway, Emilie J.; Lucas, Beth; James, Kieran D.; Parnell, Sonia M.; Carvalho-Gaspar, Manuela; White, Andrea J.; Tumanov, Alexei V.; Jenkinson, William E.; Anderson, Graham

doi:10.1084/jem.20171000

Cited by 71 publications

(108 citation statements)

References 69 publications

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“…showed that the lymphotoxin β signaling pathway controls FEZF2 expression, while TNF family members (RANKL and CD40L) have no effect. By contrast, Cosway's group showed that FEZF2 expression is regulated by the RANK transduction pathway but not by lymphotoxin β . More investigations have to be done to decipher which of these two divergent observations reflects mTEC FEZF2 gene regulation.…”

Section: Central Tolerance and Sex Hormonesmentioning

confidence: 94%

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AIRE: a missing link to explain female susceptibility to autoimmune diseases

Berrih‐Aknin

Panse

Dragin

2017

Annals of the New York Academy of Sciences

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Women are more susceptible to autoimmune diseases than men. Autoimmunity results from tolerance breakdown toward self-components. Recently, three transcription modulators were identified in medullary thymic epithelial cells that orchestrate immune central tolerance processes: the autoimmune regulator (AIRE), FEZ family zinc finger 2 (FEZF2 or FEZ1), and PR domain zinc finger protein 1 (PRDM1). Interestingly, these three transcription modulators regulate nonredundant tissue-specific antigen subsets and thus cover broad antigen diversity. Recent data from different groups demonstrated that sex hormones (estrogen and testosterone) are involved in the regulation of thymic AIRE expression in humans and mice through direct transcriptional modulation and epigenetic changes. As a consequence, AIRE displays gender-biased thymic expression, with females showing a lower expression compared with males, a finding that could explain the female susceptibility to autoimmune diseases. So far, FEZF2 has not been related to an increased gender bias in autoimmune disease. PRDM1 expression has not been shown to display gender-differential thymic expression, but its expression level and its gene polymorphisms are associated with female-dependent autoimmune disease risk. Altogether, various studies have demonstrated that increased female susceptibility to autoimmune diseases is in part a consequence of hormone-driven reduced thymic AIRE expression.

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Section: Central Tolerance and Sex Hormonesmentioning

confidence: 94%

“…Even though AIRE and FEZF2 share common features, such as coexpression and ability to regulate the expression of TSAs, their thymic expressions are differently regulated. Two groups have investigated the mechanism of regulation of FEZF2 expression in mTECs, with conflicting conclusions. Tabaka et al .…”

Section: Central Tolerance and Sex Hormonesmentioning

confidence: 99%

AIRE: a missing link to explain female susceptibility to autoimmune diseases

Berrih‐Aknin

Panse

Dragin

2017

Annals of the New York Academy of Sciences

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“…For example, mTECs are essential regulators of tolerance induction via both negative selection and Foxp3 + natural regulatory T‐cell (nT‐Reg) development. The importance of mTEC for T‐cell tolerance is highlighted in mice that lack organized medullary structures, including mTEC‐deficient Relb −/− mice, and mice lacking members of the TNFR superfamily (e.g., CD40, RANK, LTβR), all of which show signs of T‐cell‐mediated autoimmunity . Negative selection is thought to play a key role in establishing central tolerance, and involves the clonal deletion of autoreactive T‐cells to limit their escape into peripheral tissues.…”

Section: Thymus Medulla Organization For T‐cell Tolerance and Postselmentioning

confidence: 99%

“…Both Aire‐deficient mice and mice lacking Fezf2 in TECs have been shown to exhibit autoimmune deficiencies, highlighting these regulators of TRA expression as key regulators of central tolerance induction . Although the expression of Fezf2 in mTEC was thought to be regulated by lymphotoxin beta receptor (LTβR)‐signaling, a known regulator of mTEC development, further analysis of LTβR‐deficient mice revealed continued expression of both Fezf2 as well as Aire in mTEC . Interestingly, the RANK‐RANKL signaling axis initially shown to control the development of Aire + mTEC was recently found to additionally regulate development of Fezf2 + mTEC, highlighting a common developmental signaling pathway in the formation of medullary microenvironments essential for central tolerance .…”

Section: Thymus Medulla Organization For T‐cell Tolerance and Postselmentioning

confidence: 99%

“…Importantly, the thymus medulla is also rich in a heterogeneous mixture of DCs, which play a key role in both negative selection and Foxp3 + T‐cell development. Interestingly, we recently showed that an explanation for the breakdown of thymic tolerance in Ltbr −/− mice is the reduction in the size of the intrathymic DC pool rather than loss of organized LTβR‐dependent mTEC, a finding that emphasizes the importance of DC for thymic tolerance . Whether this control of thymic DC maps to the ability of this receptor to regulate CCR7 ligand expression in thymic stroma is not clear, although the survival of at least some thymic DC is regulated via CCR7 .…”

Section: Thymus Medulla Organization For T‐cell Tolerance and Postselmentioning

confidence: 99%

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T-cell egress from the thymus: Should I stay or should I go?

James

Jenkinson

Anderson

2018

Journal of Leukocyte Biology

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T‐cells bearing the αβTCR play a vital role in defending the host against foreign pathogens and malignant transformation of self. Importantly, T‐cells are required to remain tolerant to the host's own cells and tissues in order to prevent self‐reactive responses that can lead to autoimmune disease. T‐cells achieve the capacity for self/nonself discrimination by undergoing a highly selective and rigorous developmental program during their maturation in the thymus. This organ is unique in its ability to support a program of T‐cell development that ensures the establishment of a functionally diverse αβTCR repertoire within the peripheral T‐cell pool. The thymus achieves this by virtue of specialized stromal microenvironments that contain heterogeneous cell types, whose organization and function underpins their ability to educate, support, and screen different thymocyte subsets through various stages of development. These stages range from the entry of early T‐cell progenitors into the thymus, through to the positive and negative selection of the αβTCR repertoire. The importance of the thymus medulla as a site for T‐cell tolerance and the exit of newly generated T‐cells into the periphery is well established. In this review, we summarize current knowledge on the developmental pathways that take place during αβT‐cell development in the thymus. In addition, we focus on the mechanisms that regulate thymic egress and contribute to the seeding of peripheral tissues with newly selected self‐tolerant αβT‐cells.

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Assembling the thymus medulla: Development and function of epithelial cell heterogeneity

James,

Cosway,

Parnell

et al. 2023

BioEssays

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The thymus is a unique primary lymphoid organ that supports the production of self‐tolerant T‐cells essential for adaptive immunity. Intrathymic microenvironments are microanatomically compartmentalised, forming defined cortical, and medullary regions each differentially supporting critical aspects of thymus‐dependent T‐cell maturation. Importantly, the specific functional properties of thymic cortical and medullary compartments are defined by highly specialised thymic epithelial cells (TEC). For example, in the medulla heterogenous medullary TEC (mTEC) contribute to the enforcement of central tolerance by supporting deletion of autoreactive T‐cell clones, thereby counterbalancing the potential for random T‐cell receptor generation to contribute to autoimmune disease. Recent advances have further shed light on the pathways and mechanisms that control heterogeneous mTEC development and how differential mTEC functionality contributes to control self‐tolerant T‐cell development. Here we discuss recent findings in relation to mTEC development and highlight examples of how mTEC diversity contribute to thymus medulla function.

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Redefining thymus medulla specialization for central tolerance

Cited by 71 publications

References 69 publications

AIRE: a missing link to explain female susceptibility to autoimmune diseases

AIRE: a missing link to explain female susceptibility to autoimmune diseases

T-cell egress from the thymus: Should I stay or should I go?

Assembling the thymus medulla: Development and function of epithelial cell heterogeneity

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