Molecular mechanisms that regulate the formation of the thymic microenvironments
| Project/Area Number |
20390144
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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 Tokushima |
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Principal Investigator |
TAKAHAMA Yousuke The University of Tokushima, 疾患ゲノム研究センター, 教授 (20183858)
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| Co-Investigator(Kenkyū-buntansha) |
NITTA Takeshi 徳島大学, 疾患ゲノム研究センター, 講師 (30373343)
UENO Tomoo 徳島大学, 疾患ゲノム研究センター, 講師 (30360506)
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| Project Period (FY) |
2008 – 2010
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| Project Status |
Completed (Fiscal Year 2010)
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| Budget Amount *help |
¥19,630,000 (Direct Cost: ¥15,100,000、Indirect Cost: ¥4,530,000)
Fiscal Year 2010: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2009: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Fiscal Year 2008: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
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| Keywords | 免疫学 / 獲得免疫 / 胸腺分化 / 胸腺微小環境 / 胸腺上皮細胞 / 胸腺髄質上皮細胞 / 胸腺皮質上皮細胞 / ケモカイン / 胸腺プロテアソーム / ・5t / RANKL / Aire / CCR7 / XCL1 / CD40L |
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| Research Abstract |
The medullary microenvironment of the thymus plays a crucial role in the establishment of self-tolerance through the deletion of self-reactive thymocytes and the generation of regulatory T cells. Crosstalk or bidirectional signal exchanges between developing thymocytes and medullary thymic epithelial cells (mTECs) contribute to the formation of the thymic medulla. We have identified the molecules that mediate thymic crosstalk. Tumor necrosis factor superfamily cytokines, including RANKL and lymphotoxin, produced by positively selected thymocytes promote the proliferation and differentiation of mTECs. In return, CCR7 ligand chemokines produced by mTECs facilitate the migration of positively selected thymocytes to the medulla. The cytokine crosstalk between developing thymocytes and mTECs nurtures the formation of the thymic medulla and thereby regulates the establishment of self-tolerance. Our results also demonstrate that the XCL1-mediated medullary accumulation of thymic dendritic cells contributes to regulatory T cell development and is regulated by Aire and that thymoproteasome-dependent self-peptide production is required for the development of an immunocompetent repertoire of CD8+ T cells.
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Report
(4 results)
Research Products
(144 results)
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[Journal Article] Aire-dependent production of XCL1 mediates medullary accumulation of thymic dendritic cells and contributes to regulatory T cell development.2011
Author(s)
Lei Y, Mat Ripen A, Ishimaru N, Ohigashi I, Nagasawa T, Jeker L, Bosl M, Hollander GA, Hayashi Y, de Waal Malefyt R, Nitta T, Takahama Y.
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Journal Title
J Exp Med. 208
Pages: 383-394
Related Report
Peer Reviewed
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[Journal Article] Gene expression profile of third pharyngeal pouch reveals role of mesenchymal MafB in embryonic thymus development.2009
Author(s)
Sultana DA, Tomita S, Hamada M, Iwanaga Y, Kitahama Y, Khang NV, Hirai S, Ohigashi I, Nitta S, Amagai T, Takahashi S, Takahama Y.
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Journal Title
Blood. 113
Pages: 2976-2987
Related Report
Peer Reviewed
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[Journal Article]2009
Author(s)
Takeshi Nitta
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Journal Title
Systems Biology : The Challenge of Complexity(Toward understanding how the immune system establishes a diverseyet self-tolerant T-cell repertoire : stepwise roles of thymic microenvironments.)
Pages: 71-82
Related Report
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[Journal Article] The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator.2008
Author(s)
Hikosaka Y, Nitta T, Ohigashi I, Yano K, Ishimaru N, Hayashi Y, Matsumoto M, Matsuo K, Penninger JM, Takayanagi H, Yokota Y, Yamada H, Yoshikai Y, Inoue J, Akiyama T, Takahama Y.
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Journal Title
Immunity. 29
Pages: 438-450
Related Report
Peer Reviewed
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