Lymphotoxin signal promotes thymic organogenesis by eliciting RANK expression in the embryonic thymic stroma

It has recently become clear that signals mediated by members of the TNFR superfamily, including lymphotoxin-β receptor (LTβR), receptor activator for NF-κB (RANK), and CD40, play essential roles in organizing the integrity of medullary thymic epithelial cells (mTECs) required for the establishment...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2011-05, Vol.186 (9), p.5047-5057
Main Authors: Mouri, Yasuhiro, Yano, Masashi, Shinzawa, Miho, Shimo, Yusuke, Hirota, Fumiko, Nishikawa, Yumiko, Nii, Takuro, Kiyonari, Hiroshi, Abe, Takaya, Uehara, Hisanori, Izumi, Keisuke, Tamada, Koji, Chen, Lieping, Penninger, Josef M, Inoue, Jun-ichiro, Akiyama, Taishin, Matsumoto, Mitsuru
Format: Article
Language:English
Subjects:
Animals
CD40 Antigens - metabolism
Cell Differentiation - immunology
Embryo, Mammalian
Epithelial Cells - cytology
Flow Cytometry
Gene Expression
Gene Expression Regulation
Immunohistochemistry
Lymphotoxin beta Receptor - metabolism
Mice
Mice, Knockout
Organogenesis
Receptor Activator of Nuclear Factor-kappa B - biosynthesis
Reverse Transcriptase Polymerase Chain Reaction
Self Tolerance - immunology
Signal Transduction
Thymus Gland - cytology
Thymus Gland - embryology
Thymus Gland - metabolism
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Summary:It has recently become clear that signals mediated by members of the TNFR superfamily, including lymphotoxin-β receptor (LTβR), receptor activator for NF-κB (RANK), and CD40, play essential roles in organizing the integrity of medullary thymic epithelial cells (mTECs) required for the establishment of self-tolerance. However, details of the mechanism responsible for the unique and cooperative action of individual and multiple TNFR superfamily members during mTEC differentiation still remain enigmatic. In this study, we show that the LTβR signal upregulates expression of RANK in the thymic stroma, thereby promoting accessibility to the RANK ligand necessary for mTEC differentiation. Cooperation between the LTβR and RANK signals for optimal mTEC differentiation was underscored by the exaggerated defect of thymic organogenesis observed in mice doubly deficient for these signals. In contrast, we observed little cooperation between the LTβR and CD40 signals. Thus, the LTβR signal exhibits a novel and unique function in promoting RANK activity for mTEC organization, indicating a link between thymic organogenesis mediated by multiple cytokine signals and the control of autoimmunity.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1003533