Generation of diversity in thymic epithelial cells

Takahama, Yousuke; Ohigashi, Izumi; Baik, Song; Anderson, Graham

doi:10.1038/nri.2017.12

Cited by 160 publications

(168 citation statements)

References 117 publications

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“…Aire expression is largely restricted to a subset of mTECs characterized by high levels of MHCII and CD80 (mTEC hi ) [4]. Among the best characterized positive regulators of the mTEC development and maintenance are members of the tumor necrosis factor superfamily (TNF), including receptor activator of NF-kB ligand (RANKL), CD40 ligand, and Lymphotoxin (Lt), which bind their cognate receptors to activate NF-kB signaling [4]. Of note, RANKL produced by developing thymocytes is especially important for maintenance of the mTEC hi (Aire hi ) population [4].…”

Section: Aire As a Therapeutic Targetmentioning

confidence: 99%

“…Among the best characterized positive regulators of the mTEC development and maintenance are members of the tumor necrosis factor superfamily (TNF), including receptor activator of NF-kB ligand (RANKL), CD40 ligand, and Lymphotoxin (Lt), which bind their cognate receptors to activate NF-kB signaling [4]. Of note, RANKL produced by developing thymocytes is especially important for maintenance of the mTEC hi (Aire hi ) population [4]. In vivo blockade of RANKL with a neutralizing antibody not only greatly reduced mTEC cellularity but specifically reduced the mTEC hi Aire-expressing subset [48].…”

Section: Aire As a Therapeutic Targetmentioning

confidence: 99%

“…Therefore, medullary screening of TCR binding affinity provides the foundation for centrally mediated T-cell tolerance. This screening is achieved through promiscuous gene expression (PGE) of tissue-specific antigens (TSAs) by a specialized subset of medullary thymic epithelial cells (mTECs) [3,4]. Self-antigens are presented to thymocytes primarily by mTECs and medullary dendritic cells (DCs) as well as by a small subset of thymic B-cells [4,5].…”

Section: Introductionmentioning

confidence: 99%

“…This screening is achieved through promiscuous gene expression (PGE) of tissue-specific antigens (TSAs) by a specialized subset of medullary thymic epithelial cells (mTECs) [3,4]. Self-antigens are presented to thymocytes primarily by mTECs and medullary dendritic cells (DCs) as well as by a small subset of thymic B-cells [4,5]. Recent evidence has shown that this process exposes maturing thymocytes to a near complete representation of the protein coding genome, thereby ensuring the comprehensive projection of self [4].…”

Section: Introductionmentioning

confidence: 99%

“…Self-antigens are presented to thymocytes primarily by mTECs and medullary dendritic cells (DCs) as well as by a small subset of thymic B-cells [4,5]. Recent evidence has shown that this process exposes maturing thymocytes to a near complete representation of the protein coding genome, thereby ensuring the comprehensive projection of self [4]. …”

Section: Introductionmentioning

confidence: 99%

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Insights into immune tolerance from AIRE deficiency

Proekt

Miller

Lionakis

et al. 2017

Current Opinion in Immunology

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AIRE is a well-established master regulator of central tolerance. It plays an essential role in driving expression of tissue-specific antigens in the thymus and shaping the development of positively selected T-cells. Humans and mice with compromised or absent AIRE function have markedly variable phenotypes that include a range of autoimmune manifestations. Recent evidence suggests that this variability stems from cooperation of autoimmune susceptibilities involving both central and peripheral tolerance checkpoints. Here we discuss the broadening understanding of the factors that influence Aire expression, modify AIRE function, and the impact and intersection of AIRE with peripheral immunity. This rapidly expanding body of knowledge will force a reexamination of the definition and clinical management of APS-1 patients as well as provide a foundation for the development of immunomodulatory strategies targeting central tolerance.

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Section: Aire As a Therapeutic Targetmentioning

confidence: 99%

Section: Aire As a Therapeutic Targetmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Insights into immune tolerance from AIRE deficiency

Proekt

Miller

Lionakis

et al. 2017

Current Opinion in Immunology

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Deciphering tissue‐based proteome signatures revealed novel subtyping and prognostic markers for thymic epithelial tumors

Sun

Zhu

et al. 2020

Molecular Oncology

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Thymic epithelial tumors (TETs) belong to a group of tumors that rarely occur, but have unresolved mechanisms and heterogeneous clinical behaviors. Current care of TET patients demands biomarkers of high sensitivity and specificity for accurate histological classification and prognosis management. In this study, 134 fresh‐frozen tissue samples (84 tumor, 40 tumor adjacent, and 10 normal thymus) were recruited to generate a quantitative and systematic view of proteomic landscape of TETs. Among them, 90 samples were analyzed by data‐independent acquisition mass spectrometry (DIA‐MS) leading to discovery of novel classifying molecules among different TET subtypes. The correlation between clinical outcome and the identified molecules was probed, and the prioritized proteins of interest were further validated on the remaining samples (n = 44) via parallel reaction monitoring (PRM) as well as immunohistochemical and confocal imaging analysis. In particular, two proteins, the cellular mRNA deadenylase CCR4 (carbon catabolite repressor 4)‐NOT (negative on TATA) complex subunit 2/9 (CNOT2/9) and the serine hydroxymethyltransferase that catalyzes the reversible interconversions of serine and glycine (SHMT1), were found at dramatic low levels in the thymic epithelia of more malignant subtype, thymic squamous cell carcinoma (TSCC). Interestingly, the mRNA levels of these two genes were shown to be closely correlated with prognosis of the TET patients. These results extended the existing human tissue proteome atlas and allowed us to identify several new protein classifiers for TET subtyping. Newly identified subtyping and prognosis markers, CNOT2/9 and SHMT1, will expand current diagnostic arsenal in terms of higher specificity and prognostic insights for TET diagnosis and management.

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Thymus Microenvironment: Maintenance, Ageing and Strategies for Thymus Regeneration Following Damage

Alsharif¹,

Chidgey²

2022

Encyclopedia of Life Sciences

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The thymus is the major site of T‐lymphocyte production. Nonlymphoid elements, referred to as the thymic stroma, create the thymic microenvironment required to govern differentiation, maturation and tolerance induction of haematopoietic precursors into immune‐competent, nonautoreactive T cells. Thymic epithelial cells (TECs) are integral to thymopoiesis but are affected by ageing. From the onset of puberty, a proportional imbalance of TEC subpopulations coincides with a dramatic numerical loss of developing T cells. By middle‐age numerical loss of TECs accompanies further loss of thymocytes. Ongoing functional impediment of bipotent thymic epithelial progenitor cells (TEPC) has been proposed as one possible underlying cause and is more apparent in males. As such, endogenous recovery following thymic damage, such as from chemotherapy, in middle‐aged males relies heavily on proliferation of residual immature and mature TECs than through homeostatic differentiation of bipotent TEPC evident in middle‐aged females. Various strategies have been proposed to enhance thymus recovery following cytoablative therapies; however, thus far, temporary suppression of sex hormone production appears to have the most wide‐ranging impact on enhancing mature TEC replenishment and thymopoiesis. Key Concepts Thymic epithelial cells are critical for T cell development. Single‐cell transcriptomics and mapping identified more TEC subsets than first realised. Mature thymic medullary epithelial cells are essential for the presentation of self‐antigens for central tolerance induction. During age‐related thymus involution, an imbalance in TEC subsets accompanies the numerical loss of developing T cells from the onset of puberty. Postnatal bipotent thymic epithelial progenitor cells (TEPC) undergo functional attenuation from puberty with sexual dimorphism apparent. Increased reliance on activation and proliferation of enduring single‐lineage cortical and medullary TEC precursors for mature TEC maintenance during ageing. Thymic damage induces homeostatic TEC replenishment via bipotent TEPC in middle‐aged females but is restricted to proliferation and differentiation of single lineage progenitors in middle‐aged males. Temporary suppression of sex hormone production as a strategy for thymus regeneration releases the postpubertal TEPC functional block in males. Therapeutic strategies with clinical potential include adoptive transfer of in vitro generated progenitor T cells, exogenous administration of cytokines and growth factors, and temporary sex steroid inhibition.

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Generation of diversity in thymic epithelial cells

Cited by 160 publications

References 117 publications

Insights into immune tolerance from AIRE deficiency

Insights into immune tolerance from AIRE deficiency

Deciphering tissue‐based proteome signatures revealed novel subtyping and prognostic markers for thymic epithelial tumors

Thymus Microenvironment: Maintenance, Ageing and Strategies for Thymus Regeneration Following Damage

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