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The mechanism regulating the development of thymic epithelial cells

Research Project

Project/Area Number 17K08884
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Immunology
Research InstitutionThe University of Tokushima

Principal Investigator

OHIGASHI Izumi  徳島大学, 先端酵素学研究所(プロテオ), 准教授 (00596588)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords胸腺 / 胸腺上皮細胞 / プロテオーム / プロテアソーム / 精巣 / 生殖機能 / プロテオームプロファイリング / 上皮細胞 / 細胞分化 / 獲得免疫
Outline of Final Research Achievements

We did comprehensive expression analysis of cTECs and mTECs and isolated transcriptional regulators that showed significant expression difference between cTECs and mTECs. We found that mice deficient in a homeobox transcription factor highly detected in cTECs showed thymus hypoplasia and reduced expression of cTEC-genes. We also focused on PITHD1 highly detected in cTECs. PITHD1 has a putative proteasome binding domain, but is functionally unknown gene. We found that PITHD1 bind with proteasomes in the testis but not in the thymus. PITHD1-KO mice showed severe male infertility accompanied with morphological and motile abnormalities of sperm. PITHD1 deficiency reduced proteasome activity in the testis and altered the amount of proteins important for fertilization capability. However, the PITHD1-KO mice showed no detectable defects in the thymus. Collectively, our results identify PITHD1 as a proteasome-interacting protein that plays a nonredundant role in the male reproductive system.

Academic Significance and Societal Importance of the Research Achievements

本研究では、これまで技術的に困難であったcTECとmTECの網羅的なプロテオーム解析を行い、トランスクリプトームプロファイルと統合することで、これらの細胞における網羅的な発現プロファイルを明らかにした。これは、T 細胞の抗原認識特異性レパトアの形成を担う胸腺微小環境の構築機構の基盤理解に向けての有用な研究リソースになると考えられる。また、cTECとmTECの発現プロファイルから注目したPITHD1は、予想外なことに、雄性生殖能に重要なプロテアソーム会合分子であることを明らかにした。この発見は、男性不妊の原因となる分子機構の解明、および、治療法開発につながると考えられる。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (31 results)

All 2020 2019 2018 2017 Other

All Int'l Joint Research (1 results) Journal Article (12 results) (of which Int'l Joint Research: 7 results,  Peer Reviewed: 12 results,  Open Access: 11 results,  Acknowledgement Compliant: 1 results) Presentation (18 results) (of which Int'l Joint Research: 4 results)

  • [Int'l Joint Research] 米国国立衛生研究所(米国)

    • Related Report
      2019 Annual Research Report
  • [Journal Article] PITHD1 is a proteasome-interacting protein essential for male fertilization2020

    • Author(s)
      Kondo Hiroyuki、Matsumura Takafumi、Kaneko Mari、Inoue Kenichi、Kosako Hidetaka、Ikawa Masahito、Takahama Yousuke、Ohigashi Izumi
    • Journal Title

      Journal of Biological Chemistry

      Volume: 295 Issue: 6 Pages: 1658-1672

    • DOI

      10.1074/jbc.ra119.011144

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] TCR Affinity for In Vivo Peptide-Induced Thymic Positive Selection Fine-Tunes TCR Responsiveness of Peripheral CD8+ T Cells2019

    • Author(s)
      Khanom Umme Shahina、Ohigashi Izumi、Fujimori Sayumi、Kondo Kenta、Takada Kensuke、Takahama Yousuke
    • Journal Title

      The Journal of Immunology

      Volume: 203 Issue: 4 Pages: 881-887

    • DOI

      10.4049/jimmunol.1900097

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Myc controls a distinct transcriptional program in fetal thymic epithelial cells that determines thymus growth2019

    • Author(s)
      Cowan Jennifer E.、Malin Justin、Zhao Yongge、Seedhom Mina O.、Harly Christelle、Ohigashi Izumi、Kelly Michael、Takahama Yousuke、Yewdell Jonathan W.、Cam Maggie、Bhandoola Avinash
    • Journal Title

      Nature Communications

      Volume: 10 Issue: 1 Pages: 5498-5498

    • DOI

      10.1038/s41467-019-13465-y

    • NAID

      120006949467

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Trans-omics impact of thymoproteasome in cortical thymic epithelial cells.2019

    • Author(s)
      Ohigashi I, Tanaka Y, Kondo K, Fujimori S, Kondo H, Palin A, Hoffmann V, Kozai M, Matsushita Y, Uda S, Motosugi R, Hamazaki J, Kubota H, Murata S, Tanaka K, Katagiri T, Kosako H, Takahama Y
    • Journal Title

      Cell Reports

      Volume: 29 Issue: 9 Pages: 2901-2916

    • DOI

      10.1016/j.celrep.2019.10.079

    • NAID

      120006894616

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Thymoproteasome and peptidic self2019

    • Author(s)
      Takahama Y, Ohigashi I, Murata S, Tanaka K.
    • Journal Title

      Immunogenetics

      Volume: 71 Issue: 3 Pages: 217-221

    • DOI

      10.1007/s00251-018-1081-3

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Thymus machinery for T-cell selection2019

    • Author(s)
      Kondo K, Ohigashi I, Takahama Y
    • Journal Title

      International Immunology

      Volume: 31 Issue: 3 Pages: 119-125

    • DOI

      10.1093/intimm/dxy081

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] A distinct subset of fibroblastic stromal cells constitutes the cortex-medulla boundary subcompartment of the lymph node2018

    • Author(s)
      Takeuchi A, Ozawa M, Kanda Y, Kozai M, Ohigashi I, Kurosawa Y, Rahman MA, Kawamura T, Shichida Y, Umemoto E, Miyasaka M, Ludewig B, Takahama Y, Nagasawa T, Katakai T.
    • Journal Title

      Frontiers in Immunology

      Volume: 9 Pages: 2196-2196

    • DOI

      10.3389/fimmu.2018.02196

    • NAID

      120006937683

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Formation of the intrathymic dendritic cell pool requires CCL21-mediated recruitment of CCR7+ progenitors to the thymus2018

    • Author(s)
      Cosway EJ, Ohigashi I, Schauble K, Parnell SM, Jenkinson WE, Luther S, Takahama Y, Anderson G.
    • Journal Title

      The Journal of Immunology

      Volume: 201 Issue: 2 Pages: 516-523

    • DOI

      10.4049/jimmunol.1800348

    • NAID

      120006937667

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cellularity of Thymic Epithelial Cells in the Postnatal Mouse.2018

    • Author(s)
      Sakata M, Ohigashi I, Takahama Y.
    • Journal Title

      The Journal of Immunology

      Volume: 200 Pages: 1382-1388

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Essential role of CCL21 in establishment of central self-tolerance in T cells.2017

    • Author(s)
      Kozai M, Kubo Y, Katakai T, Kondo H, Kiyonari H, Schaeuble K, Luther SA, Ishimaru N, Ohigashi I, Takahama Y.
    • Journal Title

      Journal of Experimental Medicine

      Volume: 214 Issue: 7 Pages: 1925-1935

    • DOI

      10.1084/jem.20161864

    • NAID

      120006312717

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A human PSMB11 variant affects thymoproteasome processing and CD8+ T cell production2017

    • 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

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Generation of diversity in thymic epithelial cells.2017

    • Author(s)
      Takahama Y, Ohigashi I, Baik S, Anderson G.
    • Journal Title

      Nat Rev Immunol

      Volume: 印刷中 Issue: 5 Pages: 295-305

    • DOI

      10.1038/nri.2017.12

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Presentation] Trans-omics impact of thymoproteasome in cortical thymic epithelial cells2019

    • Author(s)
      Ohigashi I, Tanaka Y, kondo K, Fujimori S, Palin A, Kondo H, Kosako H, Takahama Y
    • Organizer
      ThymE: T cell and thymus biology
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Role of β-catenin in thymic epithelial progenies of β5t positive progenitors2019

    • Author(s)
      Fujimori S, Ohigashi I, Takahama Y, Takada S
    • Organizer
      ThymE: T cell and thymus biology
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] CD8T細胞の正の選択におけるペプチドスイッチ仮説の検証2019

    • Author(s)
      村松直美、大東いずみ、高浜洋介
    • Organizer
      第29回 Kyoto T cell conference
    • Related Report
      2019 Annual Research Report
  • [Presentation] 胸腺上皮細胞のオミクスプロファイリング2019

    • Author(s)
      大東いずみ、高浜洋介
    • Organizer
      第29回 Kyoto T cell conference
    • Related Report
      2019 Annual Research Report
  • [Presentation] 胸腺上皮細胞特異的なWnt/β-cateninシグナル経路活性制御の影響2019

    • Author(s)
      藤森さゆ美、大東いずみ、高田慎治、高浜洋介
    • Organizer
      第18回 四国免疫フォーラム
    • Related Report
      2019 Annual Research Report
  • [Presentation] 胸腺上皮細胞のオミクスプロファイリング2019

    • Author(s)
      大東いずみ、小迫英尊、高浜洋介
    • Organizer
      第42回 日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] マウス胸腺上皮細胞の分化にはβ-catenin依存性経路の精緻な制御が必要である2019

    • Author(s)
      藤森さゆ美、大東いずみ、高浜洋介、高田慎治、
    • Organizer
      第42回 日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 新規プロテアソーム会合因子PITHD1は精子形成を制御する2019

    • Author(s)
      近藤博之、松村貴史、小迫英尊、伊川正人、高浜洋介、大東いずみ
    • Organizer
      第42回 日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Trans-omics profiling of thymic epithelial cells2019

    • Author(s)
      Ohigashi I
    • Organizer
      The 4th Symposium of the inter-university research network for trans-omics medicine
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 胸腺皮質上皮細胞で高発現する新規分子の機能解析2018

    • Author(s)
      大東いずみ
    • Organizer
      第28回 Kyoto T cell Conference
    • Related Report
      2018 Research-status Report
  • [Presentation] プロテアソームに会合する新規分子PITHD1の機能解析2018

    • Author(s)
      近藤博之、松村貴史、小迫英尊、伊川正人、髙濵洋介、大東いずみ
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] マウス胸腺上皮細胞特異的なWnt/b-cateninシグナル経路活性化による胸腺形成異常2018

    • Author(s)
      藤森さゆ美、大東いずみ、高田慎治、髙濵洋介
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] Affinity required for positive selection to generate functional CD8+ T cells in vivo2018

    • Author(s)
      Umme Shahina Khanom, Kenta Kondo, Izumi Ohigashi and Yousuke Takahama
    • Organizer
      第17回四国免疫フォーラム
    • Related Report
      2018 Research-status Report
  • [Presentation] Human PSMB11 polymorphisms that affect thymoproteasome processing and CD8+ T cell generation2018

    • Author(s)
      Ohigashi I, Takahama Y
    • Organizer
      The 8th ThymOz
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] T細胞の自己免疫寛容確立におけるCCL21の役割2018

    • Author(s)
      大東いずみ、高浜洋介
    • Organizer
      第37回胸腺研究会
    • Related Report
      2017 Research-status Report
  • [Presentation] ヒト胸腺を用いた胸腺上皮細胞の解析2018

    • Author(s)
      松井尚子、大東いずみ、山本遥平、中川英刀、近藤和也、高浜洋介
    • Organizer
      第37回胸腺研究会
    • Related Report
      2017 Research-status Report
  • [Presentation] Essential role of CCL21 in establishment of central tolerance in T cells2017

    • Author(s)
      Ohigashi I, Ishimaru N, Katakai T, Takahama Y
    • Organizer
      第40回日本分子生物学会年会
    • Related Report
      2017 Research-status Report
  • [Presentation] マウス胸腺皮質上皮細胞亜集団におけるWnt/beta-cateninシグナル経路の活性化2017

    • Author(s)
      藤森さゆ美、大東いずみ、竹本龍也、高田慎治、高浜洋介
    • Organizer
      第40回日本分子生物学会年会
    • Related Report
      2017 Research-status Report

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Published: 2017-04-28   Modified: 2021-02-19  

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