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

2022 Fiscal Year Final Research Report

• 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
• Keywords: 先天性免疫異常症 / T細胞分化 / Bcl11b / 転写制御

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.

Free Research Field

免疫発生学

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。