The Cytokine RANKL Produced by Positively Selected Thymocytes Fosters Medullary Thymic Epithelial Cells that Express Autoimmune Regulator

Hikosaka, Yu; Nitta, Takeshi; Ohigashi, Izumi; Yano, Kouta; Ishimaru, Naozumi; Hayashi, Yoshio; Matsumoto, Machiko; Matsuo, Koichi; Penninger, Josef; Takayanagi, Hiroshi; Yokota, Yoshifumi; Yamada, Hisakata; Yoshikai, Yasunobu; Inoue, Jun; Akiyama, Taishin; Takahama, Yousuke

doi:10.1016/j.immuni.2008.06.018

Cited by 373 publications

(499 citation statements)

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“…24,25 RANK signaling was also shown to be essential for promoting the maturation of mTECs from CD80 2 to CD80 1 . [26][27][28] In addition to the development and homeostasis of mTECs, NF-kB might regulate organization of mTEC. In agreement with this, Ltbr 2/2 and Nfkb2 2/2 thymi have disorganized mTEC structure with dispersed small mTEC areas in stark contrast to the connective large mTEC area in wild-type thymi (unpublished data).…”

Section: Central Tolerancementioning

confidence: 99%

The complicated role of NF-κB in T-cell selection

Zhu

2010

Cell Mol Immunol

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The nuclear factor (NF)-kB transcription factor family plays important roles in the immune system. Aberrant NF-kB signaling is frequently associated with inflammation and autoimmune diseases but the underlying mechanisms are not fully understood. Recent studies show that NF-kB plays a critical role in T-cell central tolerance. Two NF-kB signaling pathways have been identified: the canonical pathway and the alternative pathway. In the establishment of T-cell central tolerance, the alternative pathway appears to be the key signaling component in thymic stromal cells for their development and function, while the canonical pathway exerts its function more in autonomous T-cell selection. This review intends to summarize the current understanding of the role of NF-kB in establishing T-cell central tolerance and highlight unsolved intriguing questions for future work.

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Section: Central Tolerancementioning

confidence: 99%

The complicated role of NF-κB in T-cell selection

Zhu

2010

Cell Mol Immunol

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“…At embryonic stages, it has been proposed that these cells derive from Aire À progenitors as a result of RANK-mediated signal from intrathymic lymphoid tissue inducer population [35]. In the postnatal thymus, the cellularity of Aire 1 mTEC is controlled by cooperation of CD40 and RANK signals mainly provided by CD4 1 SP thymocytes [36][37][38]. The TNF-related cytokines, lymphotoxin LTa/LTb and LTbR have also been recently shown to influence the proper organization and differentiation of mTEC without affecting the expression of Aire [39].…”

Section: Rank Signals Regulate Spatial Expression Through the Transcrmentioning

confidence: 99%

Spatial (Tbata) expression in mature medullary thymic epithelial cells

et al. 2010

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The Spatial gene is expressed in highly polarized cell types such as testis germ cells, brain neurons and thymic epithelial cells (TEC). Its expression was documented in testis and brain but poorly characterized in thymus. Here, we characterize for the first time Spatial-expressing TEC throughout ontogeny and adult mouse thymus. Spatial is expressed in thymicfated domain by embryonic day E10.5 and persists in subcapsular, cortical, medullary epithelial cells and in MTS24 1 progenitor TEC. Using mouse strains in which thymocyte development is blocked at various stages, we show that Spatial expression is independent of thymocyte-derived signals during thymus organogenesis. Analyses on purified thymic cell subsets show that Spatial short isoforms are expressed in cortical TEC (cTEC) and mature medullary TEC (mTEC). Spatial long isoforms were detected in the same TEC population. Spatial presents a nuclear distribution specific to mature mTEC expressing UEA1 and Aire. Aire-and RANKL-deficient mice revealed that Spatial expression is drastically reduced in the thymus of these mutants. These findings reveal a critical function of Aire in regulating Spatial expression, which is compatible with promiscuous Spatial gene expression. 530 IntroductionThe vertebrate thymus is responsible for the production of functional nonautoreactive T lymphocytes. In this primary lymphoid organ, T-cell precursors commonly called thymocytes undergo a series of developmental stages through interactions with thymic stromal cells, resulting in the generation of mature T lymphocytes that are exported to the periphery [1,2]. The unique function of the thymus resides mainly in the thymic epithelium, which forms the major subcompartment of the stroma [3,4]. The thymic epithelium itself is commonly divided into two main regions, the cortex and the medulla, and each of these regions contains several ultrastructurally and phenotypically distinct types of thymic epithelial cells (TEC) [5,6]. TEC are required both for thymus organogenesis and for the promotion of most if not all stages of thymocyte maturation [3,4]. Understanding the molecular mechanisms regulating TEC differentiation and function provides crucial insights into mechanisms controlling T-cell development in the thymus.Using DNA chip technology we isolated the Spatial gene (Stromal Protein Associated with Thymii and Lymph node), also known as Tbata (thymus, brain and testes associated), by an approach based on differential screening between different knock-out mice models exhibiting distinct thymic immunodeficiencies [7]. This analysis led to the identification of three adult variants of the Spatial gene expressed in the thymus [8]. In addition, we also described two other isoforms isolated in the testis [8][9][10]. According to the size of alternative spliced variants, we have respectively named Spatial isoforms: Spatial-a (1035 bp), Spatial-b (1002 bp), Spatial-g (933 bp) for the short isoforms identified in the thymus; Spatial-d (1353 bp) and Spatial-e (1454 bp) for the long isoforms ...

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“…Gene expression analysis showed that this late-appearing subpopulation of mTECs, which was identified by the CCRL1-EGFP low CD80 + phenotype, contained large amounts of Aire and RANK mRNAs but a nondetectable amount of CCL21 mRNA. Ribeiro et al [18] further demonstrate that the combination of RANK and CD40 signals, the ligands of which are produced by positively selected thymocytes [8,10], is important for the development of CCRL1-EGFP low mTECs. Thus, the analysis of CCRL1-EGFP reporter mice suggests a novel heterogeneity in postnatal mTECs.…”

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confidence: 99%

“…The temporally regulated heterogeneity of mTECs may be linked with the developmental switch of hematopoietic cells (e.g. mature thymocytes or lymphoid tissue inducer cells) that provide different cytokine ligands [8,27]. Further studies will help us understand the cellular and molecular mechanisms for the development of the heterogeneous mTEC subpopulations.…”

mentioning

confidence: 99%

CCRL1 marks heterogeneity in cortical and medullary thymic epithelial cells

Ohigashi

Takahama

2014

Eur J Immunol

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Cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells (mTECs),The shaping of T-cell repertoire that is immunocompetent (i.e. useful for self-defense) and self-tolerant (i.e. harmless to the body) is crucial for the development and maintenance of the immune system. Thymic epithelial cells (TECs), which are the major component of the thymic microenvironments, are essential for the generation and repertoire formation of T cells. The thymic cortex, which induces early T-cell development and the positive selection of functionally competent T cells, is characterized by a subset of TECs termed cortical thymic epithelial cells (cTECs), whereas the thymic medulla, which establishes self-tolerance in T cells by the negative selection of self-reactive T cells and the generation of regulatory T cells, is formed by another subset of TECs termed medullary thymic epithelial cells (mTECs). TECs are derived from the endodermal epithelium of the third pharyngeal pouch, and the transcription factor Foxn1 is required Correspondence: Prof. Yousuke Takahama e-mail: takahama@genome.tokushima-u.ac.jp for their generation [1]. The early TECs generated during embryogenesis contain bipotent progenitor thymic epithelial cells (pTECs) that are capable of generating both cTECs and mTECs [2,3]. It is acknowledged that thymocyte development differentially affects cTEC development [4][5][6] and mTEC development [7,8]. However, how pTECs branch into cTECs and mTECs and what regulates their developmental pathways are not fully understood.Several molecular markers that characterize cTECs and mTECs have been identified. For example, cTECs predominantly express keratin 8 (K8), CD205 (DEC205), and CD249 (Ly51), whereas mTECs highly express keratin 5 (K5), CD80, and molecules that bind to the lectin Ulex europaeus agglutinin 1 (UEA1) [9][10][11]. In addition, mTECs, including immature mTECs, strongly express the tight junction molecules claudin-3 and claudin-4 [12]. Molecules that define pTECs are less well known, although it was suggested that pTECs express Plet1 (MTS24) and doubly express K5 and K8 [9,13]. cTECs and mTECs have further been characterized by their expression of functional molecules. DLL4 and IL-7, whichwww.eji-journal.eu Eur. J. Immunol. 2014. 44: 2872-2875 HIGHLIGHTS 2873are important for the induction of early T-cell development, as well as the thymoproteasome subunit β5t and the serine proteasome Prss16, which are critical for the positive selection of developing thymocytes, are highly expressed by cTECs rather than mTECs [10,11]. The cytokine receptor RANK and the nuclear protein Aire, which are pivotal for mTEC development and function in establishing self-tolerance in T cells, are predominantly detectable in mTECs rather than cTECs [10,11]. Chemokines, which essentially regulate the migration of developing thymocytes, are also unequally expressed between cTECs and mTECs; CCL25 and CXCL12 are more abundant in cTECs than mTECs, whereas CCL19, CCL21, and XCL1 are more highly detectable in mTECs than cTECs [...

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The Cytokine RANKL Produced by Positively Selected Thymocytes Fosters Medullary Thymic Epithelial Cells that Express Autoimmune Regulator

Cited by 373 publications

References 55 publications

The complicated role of NF-κB in T-cell selection

The complicated role of NF-κB in T-cell selection

Spatial (Tbata) expression in mature medullary thymic epithelial cells

CCRL1 marks heterogeneity in cortical and medullary thymic epithelial cells

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