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Mechanisms and meanings of phenotypic alteration of naive CD4 T cells

Research Project

Project/Area Number 21K19393
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 49:Pathology, infection/immunology, and related fields
Research InstitutionNational Center for Global Health and Medicine

Principal Investigator

Sekiya Takashi  国立研究開発法人国立国際医療研究センター, その他部局等, 免疫応答修飾研究室長 (80519207)

Project Period (FY) 2021-07-09 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2022: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2021: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Keywords免疫学 / CD4T細胞 / 制御性T細胞 / ナイーブT細胞 / IL-1b / 自己免疫疾患
Outline of Research at the Start

CD4T細胞は、始めは機能を持たないナイーブT細胞(TN)」という形で発生し、抗原刺激を受けると、ヘルパーT細胞(Th)もしくは制御性T細胞(Treg)に分化し、的確な免疫応答を作動させる。TNは不均一な細胞集団として語られることは殆ど無かったが、研究が急速に進むにつれ、TNを均一な集団として捉えている限りは説明のつかない現象が多々見出されてきた。そこで本研究は、TNの不均一性の追求という新しい切り口から、免疫システムの理解を深めることを目的とし、ひいては、免疫関連疾患の新規治療法の開発や、効果的なワクチンの開発などの応用面の進歩に対しても手掛かりを与えることを目指す。

Outline of Final Research Achievements

Naive CD4+ T (TN) cells differentiate into helper T- or regulatory T (Treg)-cell subsets upon encountering antigens, supporting properly directed immune responses. Although all TN cells can differentiate into any Th- and Treg-cell subsets, recent studies revealed heterogeneity among TN cells. Using novel reporter mice to detect ongoing T cell receptor (TCR) signaling, we identified IL-1b signaling as a novel factor that affected TN cell characteristics, independent of tonic TCR signaling that alter TN cells. IL-1b attenuated the differentiation potential of TN cells toward Treg cells. IL-1b signaling was elevated in the splenic TN cells, attenuating their differentiation potential toward Treg cells. Aberrant elevation of IL-1b signaling augmented colitogenic activities of TN cells. Furthermore, TN cells in patients with colitis exhibited elevated IL-1b signaling. Our work revealed the phenotypic alteration of TN cells by IL-1b as a novel regulatory mechanism for immune response.

Academic Significance and Societal Importance of the Research Achievements

TN細胞の不均一性は、その重要性が証明されていないために、注目を集めていない状況にあった。しかし本研究は、疾患マウスモデルを用いた検討やヒト疾患検体データのマイニングにより、TN細胞の不均一性形成の病態生理学的意義を解明した点に、社会的意義を有する。また、免疫研究における激戦分野の一つであるヘルパーT細胞(Th)/制御性T細胞(Treg)分化の研究は急速に進められてきた一方で、TN細胞を均一な集団と捉えると説明のつかない現象も多々見出されてきていた。本研究は、TN細胞の不均一性という新たな切り口からTh/Treg分化のさらなる理解を深めた点に、一つの学術的意義を有する。

Report

(3 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • Research Products

    (5 results)

All 2023 2022 2021

All Journal Article (3 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 3 results,  Open Access: 2 results) Presentation (1 results) Book (1 results)

  • [Journal Article] Estimation of Sensitization Status in Renal Transplant Recipients by Assessing Indirect Pathway CD4+ T Cell Response to Donor Cell-pulsed Dendritic Cell2023

    • Author(s)
      Kenta Iwasaki、Toshihide Tomosugi、Takashi Sekiya、Shintaro Sakamoto、Yuko Miwa、Manabu Okada、Takahisa Hiramitsu、Norihiko Goto、Shunji Narumi、Yoshihiko Watarai、Mai Okumura、Satoshi Ashimine、Kohei Ishiyama、Ezzelarab Mohamed B.、Takaaki Kobayashi
    • Journal Title

      Transplantation

      Volume: 107 Issue: 5 Pages: 1079-1088

    • DOI

      10.1097/tp.0000000000004491

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Comparison between Nr4a transcription factor regulation and function in lymphoid and tumor Treg cells2022

    • Author(s)
      Takashi Sekiya
    • Journal Title

      Frontiers in Immunology

      Volume: in press Pages: 866339-866339

    • DOI

      10.3389/fimmu.2022.866339

    • Related Report
      2022 Annual Research Report 2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Essential roles of the transcription factor NR4A1 in regulatory T cell differentiation under the influence of immunosuppressants2022

    • Author(s)
      Takashi Sekiya, Hidenori Kasahara, Ryo Takemura, Shinya Fujita, Jun Kato, Noriko Doki, Yuta Katayama, Yukiyasu Ozawa, Satoru Takada, Tetsuya Eto, Takahiro Fukuda, Tatsuo Ichinohe, Minoko Takanashi, Makoto Onizuka, Yoshiko Atsuta, Shinichiro Okamoto, Akihiko Yoshimura, Satoshi Takaki, Takehiko Mori
    • Journal Title

      The Journal of Immunology

      Volume: in press Issue: 9 Pages: 2122-2130

    • DOI

      10.4049/jimmunol.2100808

    • Related Report
      2022 Annual Research Report 2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Tonic TCR and IL-1b signaling mediate momentary and durable phenotypic alterations in naive CD4+ T cells2022

    • Author(s)
      関谷 高史
    • Organizer
      第51回 日本免疫学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Book] Nr4aによるTh/Tregのバランス制御と炎症性疾患2021

    • Author(s)
      関谷 高史
    • Total Pages
      4
    • Publisher
      先端医学社
    • Related Report
      2021 Research-status Report

URL: 

Published: 2021-07-13   Modified: 2024-01-30  

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