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.
authors.affiliation: Division of Experimental Immunology, Institute for Genome Research, University of Tokushima, Tokushima 770-8503, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Hikosaka
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nitta
authors.forename: Izumi
authors.initials: I
authors.lastname: Ohigashi
authors.forename: Kouta
authors.initials: K
authors.lastname: Yano
authors.forename: Naozumi
authors.initials: N
authors.lastname: Ishimaru
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuo
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takayanagi
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Yokota
authors.forename: Hisakata
authors.initials: H
authors.lastname: Yamada
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Yoshikai
authors.forename: Jun-Ichiro
authors.initials: J
authors.lastname: Inoue
authors.forename: Taishin
authors.initials: T
authors.lastname: Akiyama
authors.forename: Yousuke
authors.initials: Y
authors.lastname: Takahama
mesh_terms: 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
chemical_list: 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