| Project/Area Number |
16K14648
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| Research Category |
Grant-in-Aid for Challenging Exploratory Research
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| Allocation Type | Multi-year Fund |
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| Research Field |
Medical genome science
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| Research Institution | The University of Tokyo |
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Principal Investigator |
Nitta Takeshi 東京大学, 大学院医学系研究科(医学部), 准教授 (30373343)
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| Research Collaborator |
MURO Ryunosuke 東京大学, 大学院医学系研究科, 特任研究員 (80761262)
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| Project Period (FY) |
2016-04-01 – 2018-03-31
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| Project Status |
Completed (Fiscal Year 2017)
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| Budget Amount *help |
¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | 遺伝子多様性 / 免疫学 / ゲノム / プロテアソーム / T細胞 / 自己免疫疾患 / ゲノム編集 / 遺伝子 |
|---|
| Outline of Final Research Achievements |
The thymoproteasome is a thymus-specific proteasome that contains a unique catalytic subunit PSMB11 and is essential for the development of CD8 T cells. Here we addressed whether genetic variations of human PSMB11 influence CD8 T cell selection and autoimmunity. By the computational analysis, we found that PSMB11 was highly enriched for nucleotide changes that interfere with protein function. The introduction of these ‘damaging’ variations of PSMB11 into mice by genome editing revealed that these variations impaired the development of CD8 T cells in vivo. One of the PSMB11 polymorphisms, G49S, altered the CD8 T cell repertoire in mice and is associated with a higher risk of an autoimmune disease in humans. Our findings suggest that proteasome variation exerts a significant influence on T cell repertoire selection and may contribute to the difference in individual susceptibility to autoimmunity.
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