title: Lymphotoxin signal promotes thymic organogenesis by eliciting RANK expression in the embryonic thymic stroma.
abstract: It has recently become clear that signals mediated by members of the TNFR superfamily, including lymphotoxin-β receptor (LTβR), receptor activator for NF-κB (RANK), and CD40, play essential roles in organizing the integrity of medullary thymic epithelial cells (mTECs) required for the establishment of self-tolerance. However, details of the mechanism responsible for the unique and cooperative action of individual and multiple TNFR superfamily members during mTEC differentiation still remain enigmatic. In this study, we show that the LTβR signal upregulates expression of RANK in the thymic stroma, thereby promoting accessibility to the RANK ligand necessary for mTEC differentiation. Cooperation between the LTβR and RANK signals for optimal mTEC differentiation was underscored by the exaggerated defect of thymic organogenesis observed in mice doubly deficient for these signals. In contrast, we observed little cooperation between the LTβR and CD40 signals. Thus, the LTβR signal exhibits a novel and unique function in promoting RANK activity for mTEC organization, indicating a link between thymic organogenesis mediated by multiple cytokine signals and the control of autoimmunity.
authors: Division of Molecular Immunology, Institute for Enzyme Research, The University of Tokushima, Tokushima 770-8503, Japan.
authors: Yasuhiro
authors: Y
authors: Mouri
authors: Masashi
authors: M
authors: Yano
authors: Miho
authors: M
authors: Shinzawa
authors: Yusuke
authors: Y
authors: Shimo
authors: Fumiko
authors: F
authors: Hirota
authors: Yumiko
authors: Y
authors: Nishikawa
authors: Takuro
authors: T
authors: Nii
authors: Hiroshi
authors: H
authors: Kiyonari
authors: Takaya
authors: T
authors: Abe
authors: Hisanori
authors: H
authors: Uehara
authors: Keisuke
authors: K
authors: Izumi
authors: Koji
authors: K
authors: Tamada
authors: Lieping
authors: L
authors: Chen
authors: Josef M
authors: JM
authors: Penninger
authors: Jun-ichiro
authors: J
authors: Inoue
authors: Taishin
authors: T
authors: Akiyama
authors: Mitsuru
authors: M
authors: Matsumoto
mesh_terms: D000818:Animals; D019013:CD40 Antigens / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D004622:Embryo, Mammalian; D004847:Epithelial Cells / Q000166:cytology*; D005434:Flow Cytometry; D015870:Gene Expression; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D053259:Lymphotoxin beta Receptor / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D038081:Organogenesis; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017634:Self Tolerance / Q000276:immunology; D015398:Signal Transduction; D013950:Thymus Gland / Q000166:cytology / Q000196:embryology* / Q000378:metabolism
chemical_list: D019013:CD40 Antigens; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D053246:Receptor Activator of Nuclear Factor-kappa B