Investigation of the impact of BCL11B p.N441K mutation on inborn errors of immunity

• Project/Area Number: 20K07459
• 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: Institute of Physical and Chemical Research
• Principal Investigator: Okuyama Kazuki 国立研究開発法人理化学研究所, 生命医科学研究センター, 研究員 (60712750)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 先天性免疫異常症 / T細胞分化 / Bcl11b / 転写制御 / T細胞初期分化 / ヒト原発性免疫不全症 / 原発性免疫不全症

Outline of Research at the Start

ヒト原発性免疫不全症（PID）は、単一遺伝子変異により引き起こされる先天性疾患であり、その原因は多岐に渡る。獲得免疫を担うT細胞の分化障害を伴うPIDはしばしば重篤であり、治療には骨髄移植による免疫系の再構築が求められる。近年、BCL11B遺伝子の変異がPID患者に同定されている。マウスを用いた研究からBcl11bがT細胞分化に必須の遺伝子であることが知られており、PIDにおいて極めて重要な標的遺伝子である。本研究では、BCL11B遺伝子の変異により、どのような作用機序でT細胞分化不全が誘導されるのかを、モデル動物を用いた実験で解明することを目的とする。

Outline of Final Research Achievements

A de novo mutation of BCL11B gene, p.N441K was isolated from a patient with T-lymphocytopenia. To understand the pathogenesis of p.N441K mutation, we generated a mouse model. T cell development was impaired in the mutant mice at neonatal period indicating the phenotype of the patient was recapitulated in the model mice. We found an accumulation of NK-like cells in the thymus of mutant mice suggesting that the cell fate determination toward T cell lineage was disrupted by the Bcl11b mutation. Our analyses revealed that Bcl11a is required for the repression of NK-like cells in the thymus, and mutant Bcl11b interfered Bcl11a function. The development of NK-like cells depended on Tcf1, and the mutation impaired the capacity of Bcl11b to repress Tcf1 transcriptional activity.

Academic Significance and Societal Importance of the Research Achievements

細胞の運命決定において、他の細胞系譜への分化を抑制することは極めて重要である。Bcl11bはTリンパ球系譜の運命決定を制御する最も重要な転写因子である。本研究では、胸腺内におけるNK細胞系譜への分化抑制には、Bcl11bだけではなくBcl11aも重要であることを明らかとした。

Research Products

• [Journal Article] The Majority of the Serine/Threonine Phosphorylation Sites in Bcl11b Protein Are Dispensable for the Differentiation of T Cells (2023)
  • Author(s): Okuyama Kazuki、Nomura Aneela、Nishino Kohei、Tanaka Hirokazu、Harly Christelle、Chihara Risa、Harada Yasuyo、Muroi Sawako、Kubo Masato、Kosako Hidetaka、Taniuchi Ichiro
  • Journal Title: The Journal of Immunology Volume: - Issue: 11 Pages: 1728-1739
  • DOI: 10.4049/jimmunol.2200101
  • Peer Reviewed
• [Journal Article] Three residues in the BTB domain promote a good partnership between NuRD and Thpok (2022)
  • Author(s): Okuyama Kazuki、Taniuchi Ichiro
  • Journal Title: Science Immunology Volume: 7 Issue: 72
  • DOI: 10.1126/sciimmunol.abq1408
  • Peer Reviewed
• [Journal Article] B Lymphocyte Specification Is Preceded by Extensive Epigenetic Priming in Multipotent Progenitors (2021)
  • Author(s): T. Strid, K. Okuyama, J. Tingvall-Gustafsson, J. Kuruvilla, C. Jensen, S. Lang, M. Prasad, R. Somasundaram, J. Ahsberg, S. Cristobal, S. Soneji, J Ungerback, and M. Sigvardsson
  • Journal Title: The Journal of Immunology Volume: 206 Issue: 11 Pages: 2700-2713
  • DOI: 10.4049/jimmunol.2100048
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A variant in human AIOLOS impairs adaptive immunity by interfering with IKAROS (2021)
  • Author(s): Yamashita Motoi、Kuehn Hye Sun、Okuyama Kazuki、Okada Satoshi、Inoue Yuzaburo、Takagi Masatoshi、Kanegane Hirokazu、Takeuchi Masahiro、Shimojo Naoki、Tsumura Miyuki、Padhi Aditya K.、Zhang Kam Y. J.、Boisson Bertrand、Casanova Jean-Laurent、Ohara Osamu、Rosenzweig Sergio D.、Taniuchi Ichiro、Morio Tomohiro
  • Journal Title: Nature Immunology Volume: 22 Issue: 7 Pages: 893-903
  • DOI: 10.1038/s41590-021-00951-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] T and B cell abnormalities, pneumocystis pneumonia, and chronic lymphocytic leukemia associated with an AIOLOS defect in patients (2021)
  • Author(s): Kuehn Hye Sun、Chang Jingjie、Yamashita Motoi、Niemela Julie E.、Zou Chengcheng、Okuyama Kazuki、Harada Junji、Stoddard Jennifer L.、Nunes-Santos Cristiane J.、Boast Brigette、Baxter Ryan M.、Hsieh Elena W.Y.、Garofalo Mary、Fleisher Thomas A.、Morio Tomohiro、Taniuchi Ichiro、Dutmer Cullen M.、Rosenzweig Sergio D.
  • Journal Title: Journal of Experimental Medicine Volume: 218 Issue: 12
  • DOI: 10.1084/jem.20211118
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] EBF1 and PAX5 control pro-B cell expansion via opposing regulation of the Myc gene. (2021)
  • Author(s): Somasundaram Rajesh、Jensen Christina T、Tingvall-Gustafsson Johanna、Ahsberg Josefine、Okuyama Kazuki、Prasad Mahadesh、Hagman James、Wang Xun、Soneji Shamit、Strid Tobias、Ungerback Jonas、Sigvardsson Mikael
  • Journal Title: Blood Volume: 10(1) Issue: 22 Pages: 3037-3049
  • DOI: 10.1182/blood.2020009564
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Overexpression of miR-669m inhibits erythroblast differentiation (2020)
  • Author(s): Kotaki R., et.al. Kawashima M, Yamaguchi A, Suzuki N, Koyama-Nasu R, Ogiya D, Okuyama K, Yamamoto Y, Takamatsu M, Kurosaki N, Ando K, Murata A, Ohtsuka M, Nakagawa S, Katagiri K, Kotani A.
  • Journal Title: Sci Rep. Volume: 10 Issue: 1 Pages: 13554-13554
  • DOI: 10.1038/s41598-020-70442-y
  • Peer Reviewed / Open Access
• [Journal Article] PD-L1/L2 protein levels rapidly increase on monocytes via trogocytosis from tumor cells in classical Hodgkin lymphoma (2020)
  • Author(s): Kawashima M, Carreras J, Higuchi H, Kotaki R, Hoshina T, Okuyama K, Suzuki N, Kakizaki M, Miyatake Y, Ando K, Nakayama M, Umezu S, Horie R, Higuchi Y, Katagiri K, Goyama S, Kitamura T, Chamoto K, Yano S,Nakamura N, and A Kotani
  • Journal Title: Leukemia Volume: - Issue: 9 Pages: 2405-2417
  • DOI: 10.1038/s41375-020-0737-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Interference of Bcl11a-Bcl11b heterodimer function by BCL11B p.N441K mutation during neurogenesis and thymopoiesis (2022)
  • Author(s): K. Okuyama, M. Yamashita, H. Yoshida, and I. Taniuchi
  • Organizer: The 51st Annual Meeting of the Japanese Society for Immunology
  • Invited
• [Presentation] A de novo missense mutation of Bcl11b gene causes an abnormal thymopoiesis (2021)
  • Author(s): Kazuki Okuyama, Motoi Yamashita, Kazuaki Matsumoto, Michiko Ohno-Oishi, Satoshi Kojo, Tomohiro Morio, Hideyuki Yoshida, Ichiro Taniuchi
  • Organizer: 日本免疫学会
• [Presentation] 亜鉛フィンガー転写因子Bcl11bによる遺伝子発現制御とクロマチン再構成 (2021)
  • Author(s): 奥山一生
  • Organizer: 霊長類医科学フォーラム
  • Invited