Molecular mechanisms for the maintenance of T cell differentiation potential and the determination of T cell fate

• Project/Area Number: 16K08848
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: Tokai University
• Principal Investigator: HOZUMI Katsuto 東海大学, 医学部, 教授 (30246079)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: Lmo2 / Bcl11a / Tcf1 / Notch / T細胞分化 / エピジェネティクス / Notch1 / Notchシグナル / T細胞

Outline of Final Research Achievements

We established two Ebf1-deficient pro-B cell lines possessing the different potential for the T cell differentiation. Comparing their expression profiles, Lmo2 transcripts were detected in pro-B(+) cells three-fold greater than in pro-B(-) cells, and its overexpression in pro-B(-) cells was sufficient to provide the differentiation potential. These suggested that Lmo2 has critical role to keep the differentiation potential. We found Bcl11a as a downstream target of Lmo2. Bcl11a was essential for the maintenance of cell survival via the induction of Bcl2. Moreover, Lmo2 also altered the epigenetic status of Tcf7 gene, which is necessary for the full activation of the gene locus with Notch signaling. These results suggested that Lmo2 functions to regulate both Bcl11a and Tcf1 as downstream targets and contributes to the maintenance of the competence to respond to Notch signaling at early T cell progenitor stage.

Academic Significance and Societal Importance of the Research Achievements

iPS細胞の臨床応用など、近年の再生医療の発展は顕著であるが、応用研究に利用される幹細胞の性状を分子的に理解することは、臨床応用に向けた重要な課題である。しかし、iPS細胞以外の組織幹細胞の性状はいまだに理解が不十分であり、幹細胞がどのように高い未分化性を維持できるのか明らかではない。本研究は、きわめて均一化された造血未分化細胞を用い、リンパ系細胞への分化能維持について追求したものであり、造血幹細胞移植等の発展に寄与するものと考えられる。

Research Products

• [Journal Article] Peripheral PDGFRα+gp38+ mesenchymal cells support the differentiation of fetal liver-derived ILC2. (2018)
  • Author(s): Koga, S., Hozumi, K., Hirano, K.I., Yazawa, M., Terooatea, T., Minoda, A., Nagasawa, T., Koyasu, S., and Moro, K.
  • Journal Title: J Exp Med. Volume: 215 Issue: 6 Pages: 1609-1626
  • DOI: 10.1084/jem.20172310
  • Peer Reviewed / Int'l Joint Research
• [Presentation] The epigenetic regulation of gene loci encoding transcription factor critical for the determination of T/B-cell lineages by Lmo2 (2018)
  • Author(s): Hozumi K, Hirano KI
  • Organizer: 日本免疫学会
• [Presentation] Molecular machinery for the maintenance of differentiation potential toward T/B cell lineages in hematopoietic stem/progenitor cells by Lmo2 (2017)
  • Author(s): Katsuto Hozumi, Shuhei Ochiai, Ken-ichi Hirano
  • Organizer: 日本免疫学会
• [Presentation] Essential role of Lmo2 for the maintenance of T-cell differentiation potential in Ebf1-deficient pro-B cells. (2016)
  • Author(s): Hozumi K、Ochiai S、Hirano K
  • Organizer: 日本免疫学会・学術集会
  • Place of Presentation: 沖縄コンベンションセンター（沖縄県宜野湾市）
  • Year and Date: 2016-12-05