Elucidating molecular mechanism of CD8 T cell differentiation by investigating BATF-IRF4 complex

• Project/Area Number: 19K07476
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: Kanazawa University
• Principal Investigator: Kurachi Makoto 金沢大学, 医学系, 教授 (00396722)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: CD8陽性T細胞 / 免疫記憶 / 転写調節因子

Outline of Research at the Start

本研究では、申請者がこれまでに展開してきたCTL分化および転写因子研究の優位性を基礎として、細胞免疫学・分子生物学・ゲノミクス(ATAC-seq, ChIP-seq)等の手法を組み合わせて以下の点を明らかにする。
① BATFはCTL分化のパイオニア転写因子として作用するか？
② BATFはいつ、どの領域からクロマチン構造を制御するか？
③ BATFがパイオニア転写因子として作用する分子機序（他因子との分子間相互作用）？

Outline of Final Research Achievements

To optimize the CD8-positive T cell (CTL) response, including recovery from exhaustion, molecular and time-specific interventions are important, which requires a detailed understanding of the molecular mechanisms of CTL differentiation. We used ChIP-PCR and ATAC-seq to identify epigenetic modifications regulated by BATF, and found that BATF deficiency caused differences in histone modifications and chromatin open regions. We found that BATF deficiency causes differences in histone modifications and chromatin open regions.

Academic Significance and Societal Importance of the Research Achievements

パンデミック感染症に対するワクチン開発や癌免疫療法では、最終的にはいかに強靱な抗原特異的T細胞(特にCTL)を誘導・維持できるかが鍵となる。しかし、「免疫記憶」が免疫システムにおける最も大きな特徴の一つであるにも関わらず、CTL分化の分子基盤の理解は脆弱である。これまでの細胞分化時に多数の遺伝子の発現を秩序よく調節するためには、転写因子やエピジェネティック変化はランダムではなく、連携的かつ統合的に作用する必要がある。我々のBATF機能解析成果は、CTLリプログラミングの鍵となる分子やゲノム領域を同定することを通じて、T細胞関連難治性疾患に対する新規の診断・予防・治療法の開発に貢献できる。

Research Products

• [Journal Article] Batf-mediated epigenetic control of effector CD8 ⁺ T cell differentiation (2022)
  • Author(s): Tsao Hsiao-Wei、Kaminski James、Kurachi Makoto、Barnitz R. Anthony、DiIorio Michael A.、LaFleur Martin W.、Ise Wataru、Kurosaki Tomohiro、Wherry E. John、Haining W. Nicholas、Yosef Nir
  • Journal Title: Science Immunology Volume: 7 Issue: 68
  • DOI: 10.1126/sciimmunol.abi4919
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Transient Depletion of CD4 + Cells Induces Remodeling of the TCR Repertoire in Gastrointestinal Cancer. (2021)
  • Author(s): Aoki H, Ueha S, Shichino S, Ogiwara H, Shitara K, Shimomura M, Suzuki T, Nakatsura T, Yamashita M, Kitano S, Kuroda S, Wakabayashi M, Kurachi M, Ito S, Doi T, Matsushima K.
  • Journal Title: Cancer Immunol Res. Volume: - Issue: 6 Pages: 624-636
  • DOI: 10.1158/2326-6066.cir-20-0989
  • Peer Reviewed / Open Access
• [Journal Article] Inhibitory signaling sustains a distinct early memory CD8+ T cell precursor that is resistant to DNA damage (2021)
  • Author(s): Johnnidis Jonathan B.、Muroyama Yuki、Ngiow Shin Foong、Chen Zeyu、Manne Sasikanth、Cai Zhangying、Song Shufei、Platt Jesse M.、Kurachi Makoto、Wherry E. John
  • Journal Title: Science Immunology Volume: 6 Issue: 55 Pages: 3702-3702
  • DOI: 10.1126/sciimmunol.abe3702
  • Peer Reviewed
• [Journal Article] In?vivo CD8+ T?cell CRISPR screening reveals control by Fli1 in infection and cancer (2021)
  • Author(s): Chen Zeyu、Arai Eri、Khan Omar、Zhang Zhen、Ngiow Shin Foong、He Yuan、Huang Hua、Manne Sasikanth、Cao Zhendong、Baxter Amy E.、Cai Zhangying、Freilich Elizabeth、Ali Mohammed A.、Giles Josephine R.、Wu Jennifer E.、Greenplate Allison R.、Hakeem Mohamed A.、Chen Qingzhou、Kurachi Makoto、Shi Junwei
  • Journal Title: Cell Volume: 184 Issue: 5 Pages: 1262-1280.e22
  • DOI: 10.1016/j.cell.2021.02.019
  • Peer Reviewed
• [Journal Article] Trib1 regulates T cell differentiation during chronic infection by restraining the effector program (2020)
  • Author(s): Rome Kelly S.、Stein Sarah J.、Kurachi Makoto、Petrovic Jelena、Schwartz Gregory W.、Mack Ethan A.、Uljon Sacha、Wu Winona W.、DeHart Anne G.、McClory Susan E.、Xu Lanwei、Gimotty Phyllis A.、Blacklow Stephen C.、Faryabi Robert B.、Wherry E. John、Jordan Martha S.、Pear Warren S.
  • Journal Title: Journal of Experimental Medicine Volume: 217 Issue: 5 Pages: 20190888-20190888
  • DOI: 10.1084/jem.20190888
  • Peer Reviewed
• [Journal Article] Developmental Relationships of Four Exhausted CD8+ T Cell Subsets Reveals Underlying Transcriptional and Epigenetic Landscape Control Mechanisms (2020)
  • Author(s): Beltra Jean-Christophe、Manne Sasikanth、Abdel-Hakeem Mohamed S.、Kurachi Makoto、Wherry E. John
  • Journal Title: Immunity Volume: 52 Issue: 5 Pages: 825-841.e8
  • DOI: 10.1016/j.immuni.2020.04.014
  • Peer Reviewed
• [Journal Article] MCPIP1 reduces HBV-RNA by targeting its epsilon structure (2020)
  • Author(s): Li Yingfang、Que Lusheng、Fukano Kento、Koura Miki、Kitamura Kouichi、Zheng Xin、Kato Takanobu、Aly Hussein Hassan、Watashi Koichi、Tsukuda Senko、Aizaki Hideki、Watanabe Noriyuki、Sato Yuko、Suzuki Tadaki、Suzuki Hiroshi I.、Hosomichi Kazuyoshi、Kurachi Makoto、Wakae Kousho、Muramatsu Masamichi
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 20763-20763
  • DOI: 10.1038/s41598-020-77166-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Different antiviral activities of natural APOBEC3C, APOBEC3G, and APOBEC3H variants against hepatitis B virus (2019)
  • Author(s): Kanagaraj Arun、Sakamoto Naoya、Que Lusheng、Li Yingfang、Mohiuddin Md、Koura Miki、Wakae Kousho、Kurachi Makoto、Muramatsu Masamichi、Kitamura Kouichi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 518 Issue: 1 Pages: 26-31
  • DOI: 10.1016/j.bbrc.2019.08.003
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] CXCR6 regulates localization of tissue-resident memory CD8 T cells to the airways (2019)
  • Author(s): Wein Alexander N.、McMaster Sean R.、Takamura Shiki、Dunbar Paul R.、Cartwright Emily K.、Hayward Sarah L.、McManus Daniel T.、Shimaoka Takeshi、Ueha Satoshi、Tsukui Tatsuya、Masumoto Tomoko、Kurachi Makoto、Matsushima Kouji、Kohlmeier Jacob E.
  • Journal Title: Journal of Experimental Medicine Volume: 216 Issue: 12 Pages: 2748-2762
  • DOI: 10.1084/jem.20181308
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] TCF-1-Centered Transcriptional Network Drives an Effector versus Exhausted CD8?T Cell-Fate Decision (2019)
  • Author(s): Chen Zeyu、Ji Zhicheng、Ngiow Shin Foong、Manne Sasikanth、Cai Zhangying、Huang Alexander C.、Johnson John、Staupe Ryan P.、Bengsch Bertram、Xu Caiyue、Yu Sixiang、Kurachi Makoto、et al.
  • Journal Title: Immunity Volume: 51 Issue: 5 Pages: 840-855.e5
  • DOI: 10.1016/j.immuni.2019.09.013
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Hidden Caveat of Inducible Cre Recombinase (2019)
  • Author(s): Kurachi Makoto、Ngiow Shin Foong、Kurachi Junko、Chen Zeyu、Wherry E. John
  • Journal Title: Immunity Volume: 51 Issue: 4 Pages: 591-592
  • DOI: 10.1016/j.immuni.2019.09.010
  • Peer Reviewed / Int'l Joint Research