The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator.
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.
Hikosaka
Yu
Y
Division of Experimental Immunology, Institute for Genome Research, University of Tokushima, Tokushima 770-8503, Japan.
Nitta
Takeshi
T
Ohigashi
Izumi
I
Yano
Kouta
K
Ishimaru
Naozumi
N
Hayashi
Yoshio
Y
Matsumoto
Mitsuru
M
Matsuo
Koichi
K
Penninger
Josef M
JM
Takayanagi
Hiroshi
H
Yokota
Yoshifumi
Y
Yamada
Hisakata
H
Yoshikai
Yasunobu
Y
Inoue
Jun-Ichiro
J
Akiyama
Taishin
T
Takahama
Yousuke
Y
D000818:Animals; D015551:Autoimmunity; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D053244:Osteoprotegerin / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D017634:Self Tolerance; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D000096927:AIRE Protein
D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D011948:Receptors, Antigen, T-Cell; D053221:TNF-Related Apoptosis-Inducing Ligand; D014157:Transcription Factors; D000096927:AIRE Protein