胸腺上皮幹細胞の活性制御機構の解明とその応用

• Project Area: Analysis and synthesis of multi-dimensional immune organ network
• Project/Area Number: 15H01154
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kyoto University
• Principal Investigator: 濱崎 洋子 京都大学, iPS細胞研究所, 教授 (10362477)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥11,700,000 (Direct Cost: ¥9,000,000、Indirect Cost: ¥2,700,000); Fiscal Year 2016: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2015: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
• Keywords: 胸腺 / 胸腺上皮細胞 / 胸腺上皮幹細胞 / 自己免疫疾患 / 幹細胞

Outline of Annual Research Achievements

胸腺は、獲得免疫応答の司令塔となるＴ細胞の産生と自己寛容の確立を司る中枢免疫器官である。申請者はこれまでに、中枢性自己寛容の成立を担う胸腺髄質上皮細の産生を生涯維持する髄質上皮幹細胞の同定を行ってきた。本研究の目的は、この髄質上皮幹細胞の活性を制御するメカニズムを明らかにすることにある。これまでに、ＷＴマウスでは幹細胞活性を反映するとおもわれる上皮コロニー形成能が生後直ぐに顕著に低下すること、Ｔ細胞産生がDN3で停止するRag2KOマウスでは成獣でも高く保たれることが明らかになっている。今年度は、前年度までに改良を重ね確立した成獣胸腺からのコロニーが検出可能な新たなアッセイ法を用いて、様々な遺伝子mutantマウスのコロニー形成能を調べることで、幹細胞活性の分子メカニズムとそれに関与する細胞群を明らかにすることを目指した。まず、胸腺髄質上皮細胞の発生や分化に重要な役割を果たすNFkB関連シグナルにdefectのあるnik-mutantマウス（aly/aly）について検討したところ、ＷＴとほぼ同等のコロニー形成能を示す頃が明らかとなった。以上の結果から、Nfkbシグナルは幹細胞から成熟した髄質上皮を産生するには必要なシグナルであるが、幹細胞の維持への寄与は少ないと考えられた。一方、Ｔ細胞分化が上皮側（I-Ab, B2m KOマウス）、リンパ球側（TCRa KO）の要因によりＤＰで停止するいずれのマウスにおいてもＷＴと同程度のコロニー形成能を示したことから、胸腺上皮幹細胞のコロニー形成能の低下に関わるのはＤＰ細胞である可能性が強く示唆された。現在その具体的な分子メカニズムについて検討を行っている。

Research Progress Status

28年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

28年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Impaired airway mucociliary function reduces antigen-specific IgA immune response to immunization with a claudin-4-targeting nasal vaccine in mice (2018)
  • Author(s): Suzuki H, Nagatake T, Nasu A, Lan H, Ikegami K, Setou M, Hamazaki Y, Kiyono H, Yagi K, Kondoh M, Kunisawa J
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 2904-2904
  • DOI: 10.1038/s41598-018-21120-7
  • NAID: 120006551757
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Combined effects of neoadjuvant letrozole and zoledronic acid on γδT cells in postmenopausal women with early-stage breast cancer (2018)
  • Author(s): Sugie Tomoharu、Suzuki Eiji、Yamauchi Akira、Yamagami Kazuhiko、Masuda Norikazu、Gondo Naomi、Sumi Eriko、Ikeda Takafumi、Tada Harue、Uozumi Ryuji、Kanao Shotaro、Tanaka Yoshimasa、Hamazaki Yoko、Minato Nagahiro、Toi Masakazu
  • Journal Title: Breast Volume: 38 Pages: 114-119
  • DOI: 10.1016/j.breast.2017.12.017
  • Peer Reviewed / Open Access
• [Journal Article] Bone Marrow Endothelial Cells Induce Immature and Mature B Cell Egress in Response to Erythropoietin (2017)
  • Author(s): Ito Takeshi、Hamazaki Yoko、Takaori-Kondo Akifumi、Minato Nagahiro
  • Journal Title: Cell Structure and Function Volume: 42 Issue: 2 Pages: 149-157
  • DOI: 10.1247/csf.17018
  • NAID: 130006251709
  • ISSN: 0386-7196, 1347-3700
  • Peer Reviewed / Open Access
• [Journal Article] Physiologic Thymic Involution Underlies Age-Dependent Accumulation of Senescence-Associated CD4+T Cells (2017)
  • Author(s): Sato Kyosuke、Kato Aiko、Sekai Miho、Hamazaki Yoko、Minato Nagahiro
  • Journal Title: The Journal of Immunology Volume: 199 Issue: 1 Pages: 138-148
  • DOI: 10.4049/jimmunol.1602005
  • Peer Reviewed / Open Access
• [Journal Article] A human PSMB11 variant affects thymoproteasome processing and CD8+ T cell production (2017)
  • Author(s): Ohigashi I, Ohte Y, Setoh K, Nakase H, Maekawa A, Kiyonari H, Hamazaki Y, Sekai M, Sudo T, Tabara Y, Sawai H, Omae Y, Yuliwulandari R, Tanaka Y, Mizokami M, Inoue H, Kasahara M, Minato N, Tokunaga K, Tanaka K, Matsuda F, Murata S, Takahama Y.
  • Journal Title: JCI Insight Volume: 2 Issue: 10 Pages: 1-14
  • DOI: 10.1172/jci.insight.93664
  • NAID: 120006733720
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The potential role of Osteopontin in the maintenance of commensal bacteria homeostasis in the intestine. (2017)
  • Author(s): Ito K, Nakajima A1, Fukushima Y1, Suzuki K1, Sakamoto K, Hamazaki Y, Ogasawara K, Minato N, and Hattori M.
  • Journal Title: PLoS One. Volume: 12 Issue: 3 Pages: e0173629-e0173629
  • DOI: 10.1371/journal.pone.0173629
  • NAID: 120006488574
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Obesity accelerates T-cell senescence in visceral adipose tissue (2016)
  • Author(s): Shirakawa K, Yan X, Shinmura K, Endo J, Kataoka M, Katsumata Y, Yamamoto T, Anzai A, Isobe S, Yoshida N, Itoh H, Manabe I, Sekai M, Hamazaki Y, Fukuda K, Minato N, and Sano M.
  • Journal Title: J Clin Invest. Volume: 126 Issue: 12 Pages: 4626-4639
  • DOI: 10.1172/jci88606
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Heterogeneous fibroblasts underlie age-dependent tertiary lymphoid tissues in the kidney (2016)
  • Author(s): Sato Y, Mii A, Hamazaki Y, Fujita H, Nakata H, Masuda K, Nishiyama S, Shibuya S, Haga H, Ogawa O, Shimizu A, Narumiya S, Kaisho T, Arita M, Yanagisawa M, Miyasaka M, Sharma K, Minato N, Kawamoto H, and Yanagita M.
  • Journal Title: JCI. Insight. Volume: 1 Issue: 11
  • DOI: 10.1172/jci.insight.87680
  • NAID: 120005820865
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Medullary thymic epithelial stem cells: role in thymic epithelial cell maintenance and thymic involution (2016)
  • Author(s): Hamazaki Y, Sekai M, Minato N
  • Journal Title: Immunol Rev. Volume: 271 Issue: 1 Pages: 38-55
  • DOI: 10.1111/imr.12412
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Relb acts downstream of medullary thymic epithelial stem cells and is essential for the emergence of RANK+ medullary epithelial progenitors. (2016)
  • Author(s): Baik S, Sekai M, Hamazaki Y, Jenkinson WE, Anderson G.
  • Journal Title: Eur J Immunol. Volume: - Issue: 4 Pages: 857-62
  • DOI: 10.1002/eji.201546253
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Adult thymic epithelial cell (TEC) progenitors and TEC stem cells – Models and mechanisms for the development and maintenance of thymic epithelial cells (2015)
  • Author(s): Hamazaki Y.
  • Journal Title: Eur J Immunol. Volume: 45 Issue: 11 Pages: 2985-93
  • DOI: 10.1002/eji.201545844
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Adult thymic medullary epithelium is maintained and regenerated by lineage-restricted cells rather than bipotent progenitors (2015)
  • Author(s): Ohigashi I, Zuklys S, Sakata M, Mayer CE, Hamazaki Y, Minato N, Hollander GA, Takahama Y.
  • Journal Title: Cell Rep. Volume: 13 Issue: 7 Pages: 1432-43
  • DOI: 10.1016/j.celrep.2015.10.012
  • NAID: 120006727050
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A CD153+CD4+ T follicular cell population with cell-senescence features plays a crucial role in lupus pathogenesis via osteopontin production. (2015)
  • Author(s): 1.Tahir S, Fukushima Y, Sakamoto K, Sato K, Fujita H, Inoue J, Uede T, Hamazaki Y, Hattori M, Minato N.
  • Journal Title: The Journal of Immunology Volume: 194 Issue: 12 Pages: 5725-5735
  • DOI: 10.4049/jimmunol.1500319
  • Peer Reviewed / Open Access
• [Presentation] Thymic involution and immunosenescence (2018)
  • Author(s): 濱崎洋子
  • Organizer: 第 13回 国際長寿医療研究センター 国際シンポジウム「老化研究の最前線」炎症、免疫そして認知機能の集積回路
  • Int'l Joint Research / Invited
• [Presentation] Neutrophil recruitment and activation by Hassall’s corpuscles: Implications of “sterile inflammation” in the thymic medulla (2017)
  • Author(s): Jianwei Wang, Miho Sekai, Nagahiro Minato, and Yoko Hamazaki
  • Organizer: 7th international Workshop of Kyoto T cell conference
  • Place of Presentation: 京都大学 芝蘭会館
  • Year and Date: 2017-03-14
• [Presentation] Bone marrow endothelial cells cross-present blood-borne antigens to CD8+ T cells. (2017)
  • Author(s): Takeshi Ito, Yoko Hamazaki, and Nagahiro Minato
  • Organizer: 7th international Workshop of Kyoto T cell conference
  • Place of Presentation: 京都大学 芝蘭会館
  • Year and Date: 2017-03-14
• [Presentation] Reduced thymic output and subsequent homeostatic proliferation induce phenotypic changes and enhance proinflamatory traits in naïve CD8 T cells (2017)
  • Author(s): Aiko Kato, Yoko Hamazaki, Nagahiro Minato
  • Organizer: 7th international Workshop of Kyoto T cell conference
  • Place of Presentation: 京都大学 芝蘭会館
  • Year and Date: 2017-03-14
• [Presentation] Thymopoiesis regulates clonogenic activity of thymic epithelial cells (2017)
  • Author(s): Miho Sekai, Yoko Hamazaki, Nagahiro Minato
  • Organizer: 7th international Workshop of Kyoto T cell conference
  • Place of Presentation: 京都大学 芝蘭会館
  • Year and Date: 2017-03-14
• [Presentation] 胸腺退縮と免疫老化 (2017)
  • Author(s): 濱崎洋子
  • Organizer: 第38回日本基礎老化学会シンポジウム 老化の多様性と加齢性疾患のメカニズム
• [Presentation] Thymic involution in peripheral T cell homeostasis and immunosenescence (2017)
  • Author(s): 濱崎洋子
  • Organizer: Leibniz-AMED Workshop on Immune Regulation of Diseases and Aging
• [Presentation] 免疫寛容とステルス性 (2017)
  • Author(s): 濱崎洋子
  • Organizer: 第１回 免疫ステルス公開シンポジウム
• [Presentation] Innate immune cell recruitment and activation by Hassall’s corpuscles in the thymic medulla: Implications of “sterile inflammation” on T-cell development (2017)
  • Author(s): 濱崎洋子
  • Organizer: The RIKEN IMS-JSI International Symposium on Immunology 2017 “Decoding Immune Complexity from Cell to System”
• [Presentation] 中枢性自己寛容を保証する胸腺髄質上皮細胞の発生と機能に関する研究 (2017)
  • Author(s): 濱崎洋子
  • Organizer: 花王科学賞 受賞講演
• [Presentation] ハッサル小体が関与する胸腺内好中球活性化とその意義 (2017)
  • Author(s): 濱崎洋子
  • Organizer: 第３６回日本胸腺研究会 ミニシンポジウム
• [Presentation] 胸腺退縮に伴うＴ細胞の加齢変化とその意義 (2016)
  • Author(s): 濱崎洋子
  • Organizer: 脳心血管抗加齢研究会２０１６ シンポジウム「免疫老化から迫る脳心血管疾患の発症機序」
  • Place of Presentation: 秋葉原ＵＤＸ（東京）
  • Year and Date: 2016-12-18
  • Invited
• [Presentation] Medullary thymic epithelial stem cells maintain a functional thymus to ensure lifelong central T cell tolerance (2016)
  • Author(s): Ｙｏｋｏ Ｈａｍａｚａｋｉ
  • Organizer: Swiss-Kyoto Joint Symposium “Understanding the Cellular and Molecular Mechanisms of the Robustness and Plasticity of Life”
  • Place of Presentation: 京都大学医学部・芝蘭会館
  • Year and Date: 2016-06-13
  • Int'l Joint Research / Invited
• [Presentation] 新たなＴ細胞産生の低下に伴う末梢Ｔ細胞の恒常性増殖は、ナイーブCD8 T細胞の質的変化を誘導し炎症応答を促進する (2016)
  • Author(s): 加藤愛子、濵﨑洋子、湊 長博
  • Organizer: Kyoto T cell conference 第26回学術集会
  • Place of Presentation: 延暦寺会館、京都
  • Year and Date: 2016-05-20
• [Presentation] Medullary Thymic Epithelial Stem Cells Ensuring Lifelong Central T cell Tolerance (2016)
  • Author(s): Ｙｏｋｏ Ｈａｍａｚａｋｉ
  • Organizer: Environment controlling normal and diseased hematopoietic and immune systems
  • Place of Presentation: 理化学研究所 免疫・アレルギー科学総合研究センター（RCAI）（横浜）
  • Year and Date: 2016-03-02
  • Int'l Joint Research / Invited
• [Presentation] 胸腺における中枢性自己寛容の成立と胸腺退縮に伴うＴ細胞の加齢変化 (2015)
  • Author(s): 濱崎洋子
  • Organizer: CREATE 2015（Cardio-Renal Interaction and Translational Research Enhancement）
  • Place of Presentation: ロイヤルパークホテル (東京)
  • Year and Date: 2015-07-31
  • Invited
• [Presentation] T細胞の中枢性自己寛容を生涯にわたり保証する髄質胸腺上皮幹細胞の同定 (2015)
  • Author(s): 瀬海美穂、湊長博、濱崎洋子
  • Organizer: 第６７回 日本細胞生物学会大会
  • Place of Presentation: タワーホール船堀 東京
  • Year and Date: 2015-06-30
• [Presentation] Identification and analysis of medullary thymic epithelial cells constituting Hassall’s bodies in the murine thymus (2015)
  • Author(s): Jianwei Wang、瀬海美穂、伊藤健、松井毅、 湊長博、濵﨑洋子
  • Organizer: Kyoto T cell conference 第25回学術集会
  • Place of Presentation: 京都大学 芝蘭会館
  • Year and Date: 2015-05-15
• [Book] 実験医学 2017年5月号 胸腺上皮幹細胞の早期活性低下に伴う胸腺退縮と免疫老化 (2017)
  • Author(s): 濱崎洋子 湊長博
  • Total Pages: 7
  • Publisher: 羊土社
  • ISBN: 9784758101639
• [Remarks] iPS細胞研究所HP
  • URL: http://www.cira.kyoto-u.ac.jp/j/research/hamazaki_summary.html