The cytokine RANKL produced by positively selected thymocytes Fosters medullary thymic epithelial cells that express autoimmune regulator

被引：351

作者：

Hikosaka, Yu ^{[1
]}

Nitta, Takeshi ^{[1
]}

Ohigashi, Izumi ^{[1
]}

Yano, Kouta ^{[1
]}

Ishimaru, Naozumi ^{[2
]}

Hayashi, Yoshio ^{[2
]}

Matsumoto, Mitsuru ^{[3
]}

Matsuo, Koichi ^{[4
]}

Penninger, Josef M. ^{[5
]}

Takayanagi, Hiroshi ^{[6
]}

Yokota, Yoshifumi ^{[7
]}

Yamada, Hisakata ^{[8
]}

Yoshikai, Yasunobu ^{[8
]}

Inoue, Jun-ichiro ^{[9
]}

Akiyama, Taishin ^{[9
]}

Takahama, Yousuke ^{[1
]}

机构：

[1] Univ Tokushima, Inst Genome Res, Div Expt Immunol, Tokushima 7708503, Japan

[2] Univ Tokushima, Inst Hlth Biosci, Div Oral Mol Pathol, Tokushima 7708503, Japan

[3] Univ Tokushima, Inst Enzyme Res, Div Mol Immunol, Tokushima 7708503, Japan

[4] Keio Univ, Sch Med, Dept Microbiol & Immunol, Tokyo 1608582, Japan

[5] Austrian Acad Sci, Inst Mol Biotechnol, A-1030 Vienna, Austria

[6] Tokyo Med & Dent Univ, Dept Cell Signaling, Tokyo 1138549, Japan

[7] Univ Fukui, Fac Med Sci, Div Mol Genet, Fukui 9101193, Japan

[8] Kyushu Univ, Med Inst Bioregulat, Div Host Def, Fukuoka 8128582, Japan

[9] Univ Tokyo, Inst Med Sci, Div Cellular & Mol Biol, Tokyo 1088639, Japan

来源：

IMMUNITY | 2008年 / 29卷 / 03期

关键词：

D O I：

10.1016/j.immuni.2008.06.018

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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.

引用

页码：438 / 450

页数：13

共 54 条

[1] Dependence of self-tolerance on TRAF6-directed development of thymic stroma [J].

Akiyama, T ;

Maeda, S ;

Yamane, S ;

Ogino, K ;

Kasai, M ;

Kajiura, F ;

Matsumoto, M ;

Inoue, J .

SCIENCE, 2005, 308 (5719) :248-251

[2] The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance [J].

Akiyama, Taishin ;

Shimo, Yusuke ;

Yanai, Hiromi ;

Qin, Junwen ;

Ohshima, Daisuke ;

Maruyama, Yuya ;

Asaumi, Yukiko ;

Kitazawa, Juli ;

Takayanagi, Hiroshi ;

Penninger, Josef M. ;

Matsumoto, Mitsuru ;

Nitta, Takeshi ;

Takahama, Yousuke ;

Inoue, Jun-ichiro .

IMMUNITY, 2008, 29 (03) :423-437

[3] Projection of an immunological self shadow within the thymus by the aire protein [J].

Anderson, MS ;

Venanzi, ES ;

Klein, L ;

Chen, ZB ;

Berzins, SP ;

Turley, SJ ;

von Boehmer, H ;

Bronson, R ;

Dierich, A ;

Benoist, C ;

Mathis, D .

SCIENCE, 2002, 298 (5597) :1395-1401

[4] ACTIVATION EVENTS DURING THYMIC SELECTION [J].

BENDELAC, A ;

MATZINGER, P ;

SEDER, RA ;

PAUL, WE ;

SCHWARTZ, RH .

JOURNAL OF EXPERIMENTAL MEDICINE, 1992, 175 (03) :731-742

[5] CD30/CD30 ligand (CD153) interaction regulates CD4+ T cell-mediated graft-versus-host disease [J].

Blazar, BR ;

Levy, RB ;

Mak, TW ;

Panoskaltsis-Mortari, A ;

Muta, H ;

Jones, M ;

Roskos, M ;

Serody, JS ;

Yagita, H ;

Podack, ER ;

Taylor, PA .

JOURNAL OF IMMUNOLOGY, 2004, 173 (05) :2933-2941

[6] Formation of a functional thymus initiated by a postnatal epithelial progenitor cell [J].

Bleul, Conrad C. ;

Corbeaux, Tatiana ;

Reuter, Alexander ;

Fisch, Paul ;

Moenting, Juergen Schulte ;

Boehm, Thomas .

NATURE, 2006, 441 (7096) :992-996

[7] Thymic medullary epithelial cell differentiation thymocyte emigration, and the control of autoimmunity require lymphoepithelial cross talk via LTβR [J].

Boehm, T ;

Scheu, S ;

Pfeffer, K ;

Bleul, CC .

JOURNAL OF EXPERIMENTAL MEDICINE, 2003, 198 (05) :757-769

[8] Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus [J].

Bonasio R. ;

Scimone M.L. ;

Schaerli P. ;

Grabie N. ;

Lichtman A.H. ;

von Andrian U.H. .

Nature Immunology, 2006, 7 (10) :1092-1100

[9] EXPRESSION OF RELB IS REQUIRED FOR THE DEVELOPMENT OF THYMIC MEDULLA AND DENDRITIC CELLS [J].

BURKLY, L ;

HESSION, C ;

OGATA, L ;

REILLY, C ;

MARCONI, LA ;

OLSON, D ;

TIZARD, R ;

CATE, R ;

LO, D .

NATURE, 1995, 373 (6514) :531-536

[10] Lymphotoxin pathway directs thymic Aire expression [J].

Chin, RK ;

Lo, JC ;

Kim, O ;

Blink, SE ;

Christiansen, PA ;

Peterson, P ;

Wang, Y ;

Ware, C ;

Fu, YX .

NATURE IMMUNOLOGY, 2003, 4 (11) :1121-1127

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