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

doi:10.1016/j.immuni.2008.06.018

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

Faculty of Medical Sciences

Research output: Contribution to journal › Article › peer-review

343 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 language	English
Pages (from-to)	438-450
Number of pages	13
Journal	Immunity
Volume	29
Issue number	3
DOIs	https://doi.org/10.1016/j.immuni.2008.06.018
Publication status	Published - Sept 19 2008

All Science Journal Classification (ASJC) codes

Immunology and Allergy
Immunology
Infectious Diseases

UN SDGs

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10.1016/j.immuni.2008.06.018

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Hikosaka, Y., Nitta, T., Ohigashi, I., Yano, K., Ishimaru, N., Hayashi, Y., Matsumoto, M., Matsuo, K., Penninger, J. M., Takayanagi, H., Yokota, Y., Yamada, H., Yoshikai, Y., Inoue, J. I., Akiyama, T., & Takahama, Y. (2008). The Cytokine RANKL Produced by Positively Selected Thymocytes Fosters Medullary Thymic Epithelial Cells that Express Autoimmune Regulator. Immunity, 29(3), 438-450. https://doi.org/10.1016/j.immuni.2008.06.018

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

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

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.",

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

note = "Funding Information: We thank H. Kikutani, T. Yasui, K. Sugamura, N. Ishii, D. Littman, S. Fagarasan, E. Podack, I. Negishi, S. Itohara, and M. Nanno for generously providing us the mice used in this study. We thank H. Nakase, T. Ueno, and Q. Cui for critically reading the manuscript. Technical support by S. Nitta is acknowledged. This study was supported by MEXT Grant-in-Aid for Scientific Research on Priority Areas “Immunological Self” and the Mitsubishi Foundation. Y.H. is a visiting graduate student from Nagoya City University Graduate School of Medical Sciences. T.N. is a JSPS Research Fellow. ",

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doi = "10.1016/j.immuni.2008.06.018",

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AU - Hikosaka, Yu

AU - Nitta, Takeshi

AU - Ohigashi, Izumi

AU - Yano, Kouta

AU - Ishimaru, Naozumi

AU - Hayashi, Yoshio

AU - Matsumoto, Mitsuru

AU - Matsuo, Koichi

AU - Penninger, Josef M.

AU - Takayanagi, Hiroshi

AU - Yokota, Yoshifumi

AU - Yamada, Hisakata

AU - Yoshikai, Yasunobu

AU - Inoue, Jun ichiro

AU - Akiyama, Taishin

AU - Takahama, Yousuke

N1 - Funding Information: We thank H. Kikutani, T. Yasui, K. Sugamura, N. Ishii, D. Littman, S. Fagarasan, E. Podack, I. Negishi, S. Itohara, and M. Nanno for generously providing us the mice used in this study. We thank H. Nakase, T. Ueno, and Q. Cui for critically reading the manuscript. Technical support by S. Nitta is acknowledged. This study was supported by MEXT Grant-in-Aid for Scientific Research on Priority Areas “Immunological Self” and the Mitsubishi Foundation. Y.H. is a visiting graduate student from Nagoya City University Graduate School of Medical Sciences. T.N. is a JSPS Research Fellow.

PY - 2008/9/19

Y1 - 2008/9/19

N2 - 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.

AB - 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.

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

Abstract

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