| Project/Area Number |
18390150
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Immunology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
AKIYAMA Taishin The University of Tokyo, Institute of Medical Science, Associate Professor (50327665)
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| Co-Investigator(Kenkyū-buntansha) |
INOUE Jun-ichiro The University of Tokyo, Institute of Medical Science, Professor (70176428)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥16,490,000 (Direct Cost: ¥14,900,000、Indirect Cost: ¥1,590,000)
Fiscal Year 2007: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
Fiscal Year 2006: ¥9,600,000 (Direct Cost: ¥9,600,000)
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| Keywords | Immunology / Signal transduction / Regulation of expression / Development & differentiation / Cell & organs |
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| Research Abstract |
Clonal deletion is one of the main mechanisms maintaining T-cell tolerance to prevent autoimmunity. Several lines of evidence suggest that establishment of T-cell tolerance requires medullary thymic epithelial cells (mTECs) in thymus. mTECs have a unique property to "promiscuously" express peripheral tissue specific antigens (TSAs). It is proposed that mTECs present TSAs to T-cells in order to eliminate self-organ specific T-cells. The TSA expression in mTECs is in part regulated by autoimmune regulator (Aire), which is responsible for human autoimmune disorder. Several studies indicate that development of Aire- and TSAs-expressing mTECs is controlled by NF-κB activation signal. Indeed, we showed that the development of Aire- and TSAs-positive mTECs depends on TNF receptor-associated factor 6 (TRAF6), a signal transducer activating NF-κB pathways. However, receptor to regulate mTEC development via TRAF6- dependent NF-κB activation remains to be determined. Since TRAF6 transduces the signal from TNF-family receptors, we investigated the expression profile of this receptor family in fetal thymic stroma. As result, we obtained the two candidates, receptor activator of NF-κB (RANK) and CD40. Whereas defect of mTEC development is partial in each single mutant mice deficient in RANK ligand (RANKL) or CD40. mTEC development and expression of Aire and TSAs were abolished in RANKL and CD40 doubly deficient mice (DKO). In addition, transfer of splenocytes from DKO induced severe autoimmunity in recipients. These data strongly suggest that RANK and CD40 cooperatively control mTEC development essential for self-tolerance. We also found that ligation of RANK or CD40 with recombinant ligand is sufficient for the development of mTECs in thymic stroma culture. Furthermore, the mTEC development via RANK or CD40 ligation depends on TRAF6, NF-κB inducing kinase, and RelB. Therefore, our study delineates the signal pathway required for the mTEC development.
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