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

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

Research output: Contribution to journalArticle

262 Citations (Scopus)

Abstract

The thymic medulla provides a microenvironment where medullary thymic epithelial cells (mTECs) express autoimmune regulator and diverse tissue-restricted genes, contributing to launching self-tolerance. Positive selection is essential for thymic medulla formation via a previously unknown mechanism. Here we show that the cytokine RANK ligand (RANKL) was produced by positively selected thymocytes and regulated the cellularity of mTEC by interacting with RANK and osteoprotegerin. Forced expression of RANKL restored thymic medulla in mice lacking positive selection, whereas RANKL perturbation impaired medulla formation. These results indicate that RANKL produced by positively selected thymocytes is responsible for fostering thymic medulla formation, thereby establishing central tolerance.

Original languageEnglish
Pages (from-to)438-450
Number of pages13
JournalImmunity
Volume29
Issue number3
DOIs
Publication statusPublished - 2008 Sep 19

Fingerprint

RANK Ligand
Thymocytes
Epithelial Cells
Cytokines
Central Tolerance
Self Tolerance
Osteoprotegerin
Foster Home Care
Genes

Keywords

  • CELLIMMUNO
  • MOLIMMUNO

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases
  • Immunology

Cite this

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, Mitsuru; Matsuo, Koichi; Penninger, Josef M.; Takayanagi, Hiroshi; Yokota, Yoshifumi; Yamada, Hisakata; Yoshikai, Yasunobu; Inoue, Jun ichiro; Akiyama, Taishin; Takahama, Yousuke.

In: Immunity, Vol. 29, No. 3, 19.09.2008, p. 438-450.

Research output: Contribution to journalArticle

Hikosaka, Y, Nitta, T, Ohigashi, I, Yano, K, Ishimaru, N, Hayashi, Y, Matsumoto, M, Matsuo, K, Penninger, JM, Takayanagi, H, Yokota, Y, Yamada, H, Yoshikai, Y, Inoue, JI, Akiyama, T & Takahama, Y 2008, 'The Cytokine RANKL Produced by Positively Selected Thymocytes Fosters Medullary Thymic Epithelial Cells that Express Autoimmune Regulator', Immunity, vol. 29, no. 3, pp. 438-450. https://doi.org/10.1016/j.immuni.2008.06.018
Hikosaka, Yu ; Nitta, Takeshi ; Ohigashi, Izumi ; Yano, Kouta ; Ishimaru, Naozumi ; Hayashi, Yoshio ; Matsumoto, Mitsuru ; Matsuo, Koichi ; Penninger, Josef M. ; Takayanagi, Hiroshi ; Yokota, Yoshifumi ; Yamada, Hisakata ; Yoshikai, Yasunobu ; Inoue, Jun ichiro ; Akiyama, Taishin ; Takahama, Yousuke. / The Cytokine RANKL Produced by Positively Selected Thymocytes Fosters Medullary Thymic Epithelial Cells that Express Autoimmune Regulator. In: Immunity. 2008 ; Vol. 29, No. 3. pp. 438-450.
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