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

Yasuhiro Mouri, Masashi Yano, Miho Shinzawa, Yusuke Shimo, Fumiko Hirota, Yumiko Nishikawa, Takuro Nii, Hiroshi Kiyonari, Takaya Abe, Hisanori Uehara, Keisuke Izumi, Koji Tamada, Lieping Chen, Josef M. Penninger, Jun Ichiro Inoue, Taishin Akiyama, Mitsuru Matsumoto

Research output: Contribution to journalArticlepeer-review

64 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)5047-5057
Number of pages11
JournalJournal of Immunology
Issue number9
StatePublished - May 1 2011

ASJC Scopus subject areas

  • Immunology


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