TY - JOUR
T1 - Lymphotoxin signal promotes thymic organogenesis by eliciting RANK expression in the embryonic thymic stroma
AU - Mouri, Yasuhiro
AU - Yano, Masashi
AU - Shinzawa, Miho
AU - Shimo, Yusuke
AU - Hirota, Fumiko
AU - Nishikawa, Yumiko
AU - Nii, Takuro
AU - Kiyonari, Hiroshi
AU - Abe, Takaya
AU - Uehara, Hisanori
AU - Izumi, Keisuke
AU - Tamada, Koji
AU - Chen, Lieping
AU - Penninger, Josef M.
AU - Inoue, Jun Ichiro
AU - Akiyama, Taishin
AU - Matsumoto, Mitsuru
PY - 2011/5/1
Y1 - 2011/5/1
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.1003533
DO - 10.4049/jimmunol.1003533
M3 - Article
C2 - 21441458
AN - SCOPUS:79955549011
SN - 0022-1767
VL - 186
SP - 5047
EP - 5057
JO - Journal of Immunology
JF - Journal of Immunology
IS - 9
ER -