2021 Fiscal Year Final Research Report
The Cxxc1 subunit of the Trithorax complex directs epigenetic licensing of CD4+ T cell differentiation
| Project/Area Number |
19K16683
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 49070:Immunology-related
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| Research Institution | Chiba University |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Keywords | 免疫 / ヘルパーT細胞 / エピジェネティクス / TCR / H3K4メチル化 / CXXC1 / Th2 |
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| Outline of Final Research Achievements |
In T cells, genes that are turned on early or turned off and stay off have been thoroughly studied. However, genes that are initially turned off but then turned on again after stimulation has ceased have not been defined; they are obviously important, especially in the context of acute versus chronic inflammation. Using the Th1/Th2 differentiation paradigm, we found that the Cxxc1 subunit of the Trithorax complex directs transcription of genes initially down-regulated by TCR stimulation but up-regulated again in a later phase. The late up-regulation of these genes was impaired either by prolonged TCR stimulation or Cxxc1 deficiency, which led to decreased expression of Trib3 and Klf2 in Th1 and Th2 cells, respectively. Loss of Cxxc1 resulted in enhanced pathogenicity in allergic airway inflammation in vivo. Thus, Cxxc1 plays essential roles in the establishment of a proper CD4+ T cell immune system via epigenetic control of a specific set of genes.
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| Free Research Field |
ライフサイエンス / 免疫学
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| Academic Significance and Societal Importance of the Research Achievements |
本研究により、T細胞活性化の後期段階における分化シグナルの離脱が、適切な機能分化に重要なエピジェネティックな変化を誘導する重要であることが明らかになった。また、Cxxc1は、CD4+T細胞が免疫力の高いTh1およびTh2細胞に分化する際のエピジェネティックな変化の中心的な役割を果たしていると考えられる。このような現象は、エピジェネティックな免疫チェックポイントとして考えられ、従来の免疫抑制受容体を介する機構とは異なる新規のブレーキ機構であることが考えられる。このようなエピジェネティックな免疫チェックポイントを標的とすることで腫瘍免疫などの免疫賦活化治療に適用できることが期待される。
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