Transcriptional regulation of Treg development and function

• Project/Area Number: 18K15201
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: Okinawa Institute of Science and Technology Graduate University
• Principal Investigator: Koizumi Shin-ichi 沖縄科学技術大学院大学, 免疫シグナルユニット, 研究員 (70636547)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 制御性Ｔ細胞 / Treg / 転写因子 / JunB / エフェクター型制御性Ｔ細胞 / 自己免疫疾患 / ChIP-seq / effector Treg / 制御性T細胞 / エフェクター型制御性T細胞 / eTreg / 皮膚免疫 / 組織特異的免疫応答

Outline of Final Research Achievements

Regulatory T (Treg) cells need to differentiate into effector Treg (eTreg) cells to maintain immune homeostasis. I elucidated that the AP-1 transcription factor JunB is expressed in eTreg cells and promotes an IRF4-dependent transcription program. Mice lacking JunB in Treg cells develop multi-organ autoimmunity, concomitant with aberrant activation of T helper cells. JunB promotes expression of Treg effector molecules, such as ICOS and CTLA4, in BATF-dependent and BATF-independent manners, and is also required for homeostasis and suppressive functions of eTreg. Mechanistically, JunB facilitates the accumulation of IRF4 at a subset of IRF4 target sites, including those located near Icos and Ctla4. Thus, JunB is a critical regulator of IRF4-dependent Treg effector programs, highlighting important functions for AP-1 in Treg-mediated immune homeostasis.

Academic Significance and Societal Importance of the Research Achievements

本研究により、エフェクターTregの転写制御機構の一端が明らかとなった。本研究成果は、Treg、特にエフェクターTregの機能制御を介した自己免疫疾患の治療法の開発へとつながることが予想される。またそれに加え、Tregの機能を部分的に抑制することによる、副作用の少ないがん免疫療法の開発へとつながる可能性もある。

Research Products

• [Journal Article] Transcriptional Regulation of Differentiation and Functions of Effector T Regulatory Cells (2019)
  • Author(s): Koizumi S and Ishikawa H
  • Journal Title: Cells Volume: 8 Issue: 8 Pages: 939-939
  • DOI: 10.3390/cells8080939
  • Peer Reviewed / Open Access
• [Journal Article] JunB regulates homeostasis and suppressive functions of effector regulatory T cells. (2018)
  • Author(s): Koizumi SI, Sasaki D, Hsieh TH, Taira N, Arakaki N, Yamasaki S, Wang K, Sarkar S, Shirahata H, Miyagi M, Ishikawa H.
  • Journal Title: Nature communications Volume: 17 Issue: 1 Pages: 1-14
  • DOI: 10.1038/s41467-018-07735-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 転写因子JunBはEffector型制御性T細胞の機能と維持に必須の役割を果たす (2018)
  • Author(s): 小泉 真一、佐々木 大樹、石川 裕規
  • Organizer: 日本分子生物学会
• [Presentation] Transcription factor JunB is essential for effector regulatory T cells homeostasis and function (2018)
  • Author(s): Shin-ichi Koizumi, Hiroki Ishikawa
  • Organizer: 日本免疫学会
• [Remarks] 過剰な免疫反応を抑えるための新たなブレーキ制御メカニズムの発見
  • URL: https://www.oist.jp/ja/news-center/press-releases/33433