Limitation of immune tolerance-inducing thymic epithelial cell development by Spi-B-mediated negative feedback regulation.
Medullary thymic epithelial cells (mTECs) expressing the autoimmune regulator AIRE and various tissue-specific antigens (TSAs) are critical for preventing the onset of autoimmunity and may attenuate tumor immunity. However, molecular mechanisms controlling mTEC development remain elusive. Here, we describe the roles of the transcription factor Spi-B in mTEC development. Spi-B is rapidly up-regulated by receptor activator of NF-κB ligand (RANKL) cytokine signaling, which triggers mTEC differentiation, and in turn up-regulates CD80, CD86, some TSAs, and the natural inhibitor of RANKL signaling, osteoprotegerin (OPG). Spi-B-mediated OPG expression limits mTEC development in neonates but not in embryos, suggesting developmental stage-specific negative feedback regulation. OPG-mediated negative regulation attenuates cellularity of thymic regulatory T cells and tumor development in vivo. Hence, these data suggest that this negative RANKL-Spi-B-OPG feedback mechanism finely tunes mTEC development and function and may optimize the trade-off between prevention of autoimmunity and induction of antitumor immunity.
Division of Cellular and Molecular Biology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Nobuko
N
Akiyama
Division of Cellular and Molecular Biology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Miho
M
Shinzawa
Division of Cellular and Molecular Biology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Maki
M
Miyauchi
Division of Cellular and Molecular Biology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Hiromi
H
Yanai
Division of Cellular and Molecular Biology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Ryosuke
R
Tateishi
Division of Cellular and Molecular Biology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Yusuke
Y
Shimo
Division of Cellular and Molecular Biology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Daisuke
D
Ohshima
Laboratory of Cell and Tissue Biology, Graduate School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan.
Koichi
K
Matsuo
Laboratory for Immune Regulation, World Premier International Research Center Initiative, Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
Izumi
I
Sasaki
Laboratory for Immune Regulation, World Premier International Research Center Initiative, Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan Laboratory for Inflammatory Regulation, Research Center for Allergy and Immunology, RIKEN Center for Integrative Medical Sciences, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan Department of Immunology, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa 761-0793, Japan.
Katsuaki
K
Hoshino
Laboratory of Cellular Biochemistry, Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
Guoying
G
Wu
Laboratory of Cellular Biochemistry, Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
Shintaro
S
Yagi
Division of Cellular and Molecular Biology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Jun-ichiro
J
Inoue
Laboratory for Immune Regulation, World Premier International Research Center Initiative, Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan Laboratory for Inflammatory Regulation, Research Center for Allergy and Immunology, RIKEN Center for Integrative Medical Sciences, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan taishin@ims.u-tokyo.ac.jp tkaisho@wakayama-med.ac.jp.
Tsuneyasu
T
Kaisho
Division of Cellular and Molecular Biology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan taishin@ims.u-tokyo.ac.jp tkaisho@wakayama-med.ac.jp.
Taishin
T
Akiyama
D000818:Animals; D000831:Animals, Newborn; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism; D025461:Feedback, Physiological; D005260:Female; D015870:Gene Expression / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053244:Osteoprotegerin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053245:RANK Ligand / Q000276:immunology / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology* / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
D018122:B7-1 Antigen; D053244:Osteoprotegerin; D017346:Protein Serine-Threonine Kinases; D050783:Proto-Oncogene Proteins c-ets; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D000097782:NF-kappaB-Inducing Kinase; C514177:Spi-B protein, mouse