Lymphotoxin Signal Promotes Thymic Organogenesis by Eliciting RANK Expression in the Embryonic Thymic Stroma

Mouri, Yasuhiro; Yano, Masashi; Shinzawa, Miho; Shimo, Yusuke; Hirota, Fumiko; Nishikawa, Yumiko; Nii, Takuro; Kanazawa, Hiroshi; Abe, Takaya; Uehara, Hisanori; Izumi, Kiyotaka; Tamada, Koji; Chen, Lieping; Penninger, Josef; Inoue, Jun; Akiyama, Taishin; Matsumoto, Machiko

doi:10.4049/jimmunol.1003533

Cited by 78 publications

(75 citation statements)

References 56 publications

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“…Thus, the development of CCL21-expressing TECs during embryogenesis occurs earlier than that of Aire-expressing TECs and may be regulated independently of Aire. During the embryogenesis, LTbR may also assume a different role in TECs by promoting RANK expression (34).…”

Section: Discussionmentioning

confidence: 99%

Lymphotoxin β Receptor Regulates the Development of CCL21-Expressing Subset of Postnatal Medullary Thymic Epithelial Cells

Lkhagvasuren

Sakata

Ohigashi

et al. 2013

The Journal of Immunology

114

111

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Medullary thymic epithelial cells (mTECs) play a pivotal role in the establishment of self-tolerance in T cells by ectopically expressing various tissue-restricted self-Ags and by chemoattracting developing thymocytes. The nuclear protein Aire expressed by mTECs contributes to the promiscuous expression of self-Ags, whereas CCR7-ligand (CCR7L) chemokines expressed by mTECs are responsible for the attraction of positively selected thymocytes. It is known that lymphotoxin signals from the positively selected thymocytes preferentially promote the expression of CCR7L rather than Aire in postnatal mTECs. However, it is unknown how lymphotoxin signals differentially regulate the expression of CCR7L and Aire in mTECs and whether CCR7L-expressing mTECs and Aire-expressing mTECs are distinct populations. In this study, we show that the majority of postnatal mTECs that express CCL21, a CCR7L chemokine, represent an mTEC subpopulation distinct from the Aire-expressing mTEC subpopulation. Interestingly, the development of CCL21-expressing mTECs, but not Aire-expressing mTECs, is impaired in mice deficient in the lymphotoxin β receptor. These results indicate that postnatal mTECs consist of heterogeneous subsets that differ in the expression of CCL21 and Aire, and that lymphotoxin β receptor regulates the development of the CCL21-expressing subset rather than the Aire-expressing subset of postnatal mTECs.

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Section: Discussionmentioning

confidence: 99%

Lymphotoxin β Receptor Regulates the Development of CCL21-Expressing Subset of Postnatal Medullary Thymic Epithelial Cells

Lkhagvasuren

Sakata

Ohigashi

et al. 2013

The Journal of Immunology

114

111

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“…Fetal thymus organ culture (FTOC) was performed as described previously (13). Thymic lobes were cultured in media containing recombinant RANKL (1 mg/ml; Oriental Yeast) and/or DT (500 ng/ml; Sigma) for 7 d.…”

Section: Fetal Thymus Organ Culturementioning

confidence: 99%

“…Preparation of TECs and flow cytometric analysis with a FACSAria II (BD) and a Gallios (Beckman Coulter) were performed as described previously (13). The mAbs used were anti-CD45, anti-EpCAM, anti-IA b , and anti-CD80 (all from eBioscience).…”

Section: Thymic Epithelial Cell Preparation and Flow Cytometric Analysismentioning

confidence: 99%

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Aire Expression Is Inherent to Most Medullary Thymic Epithelial Cells during Their Differentiation Program

Kawano

Nishijima

Morimoto

et al. 2015

The Journal of Immunology

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Aire in medullary thymic epithelial cells (mTECs) plays an important role in the establishment of self-tolerance. Because Aire+ mTECs appear to be a limited subset, they may constitute a unique lineage(s) among mTECs. An alternative possibility is that all mTECs are committed to express Aire in principle, but Aire expression by individual mTECs is conditional. To investigate this issue, we established a novel Aire reporter strain in which endogenous Aire is replaced by the human AIRE-GFP-Flag tag (Aire/hAGF-knockin) fusion gene. The hAGF reporter protein was produced and retained very efficiently within mTECs as authentic Aire nuclear dot protein. Remarkably, snapshot analysis revealed that mTECs expressing hAGF accounted for >95% of mature mTECs, suggesting that Aire expression does not represent a particular mTEC lineage(s). We confirmed this by generating Aire/diphtheria toxin receptor–knockin mice in which long-term ablation of Aire+ mTECs by diphtheria toxin treatment resulted in the loss of most mature mTECs beyond the proportion of those apparently expressing Aire. These results suggest that Aire expression is inherent to all mTECs but may occur at particular stage(s) and/or cellular states during their differentiation, thus accounting for the broad impact of Aire on the promiscuous gene expression of mTECs.

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“…Canonical and noncanonical NF-kB molecules and their regulators IKKα, IKKβ, NIK, and TRAF6 are required for mTEC development through CD40, RANK, and LTβR of the TNFR family receptors ( Table 1). [25,[31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] Notably, excepting IKKα, mice deficient in these molecules develop impaired central tolerance-associated autoimmune diseases, but they do not display manifestations with increased fungal infection and carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

Integrity of IKK/NF‐κB Shields Thymic Stroma That Suppresses Susceptibility to Autoimmunity, Fungal Infection, and Carcinogenesis

Zhu

2018

BioEssays

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A pathogenic connection between autoreactive T cells, fungal infection, and carcinogenesis has been demonstrated in studies of human autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) as well as in a mouse model in which kinase-dead Ikkα knock-in mice develop impaired central tolerance, autoreactive T cell-mediated autoimmunity, chronic fungal infection, and esophageal squamous cell carcinoma, which recapitulates APECED. IkB kinase α (IKKα) is one subunit of the IKK complex required for NF-kB activation. IKK/NF-kB is essential for central tolerance establishment by regulating the development of medullary thymic epithelial cells (mTECs) that facilitate the deletion of autoreactive T cells in the thymus. In this review, we extensively discuss the pathogenic roles of inborn errors in the IKK/NF-kB loci in the phenotypically related diseases APECED, immune deficiency syndrome, and severe combined immunodeficiency; differentiate how IKK/NF-kB components, through mTEC (stroma), T cells/leukocytes, or epithelial cells, contribute to the pathogenesis of infectious diseases, autoimmunity, and cancer; and highlight the medical significance of IKK/NF-kB in these diseases.

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Lymphotoxin Signal Promotes Thymic Organogenesis by Eliciting RANK Expression in the Embryonic Thymic Stroma

Cited by 78 publications

References 56 publications

Lymphotoxin β Receptor Regulates the Development of CCL21-Expressing Subset of Postnatal Medullary Thymic Epithelial Cells

Lymphotoxin β Receptor Regulates the Development of CCL21-Expressing Subset of Postnatal Medullary Thymic Epithelial Cells

Aire Expression Is Inherent to Most Medullary Thymic Epithelial Cells during Their Differentiation Program

Integrity of IKK/NF‐κB Shields Thymic Stroma That Suppresses Susceptibility to Autoimmunity, Fungal Infection, and Carcinogenesis

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