The role of DNA demethylase TET in Treg/Th17 differentiation.

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07541
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: Chiba University (2022); Keio University (2020-2021)
• Principal Investigator: Nakatsukasa Hiroko 千葉大学, 大学院薬学研究院, 准教授 (90749334)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: DNAメチル化 / Th17細胞 / 制御性T細胞 / エピジェネティクス / TET

Outline of Final Research Achievements

Ten-eleven translocation (TET) proteins regulate DNA methylation and gene expression. Previously we found that T cell-specific Tet2 and Tet3 double-knockout (Tet2f/fTet3f/fCd4-Cre; DKO) mice displayed splenomegaly and lymph adenopathy accompanied by uncontrolled activation of T cells which exhibited Th17- and/or follicular helper T (Tfh)-like phenotypes. In this study, we revealed that Tet2 and Tet3 regulate Treg/Th17 differentiation in the periphery. We found that Tet regulates Treg/Th17 differentiation via AhR signaling by gut microbiota-dependent tryptophan metabolites. Furthermore, gene expression and methylation analysis revealed that Tet regulates Th17 differentiation through DNA methylation of the Rara and Bach2 genes.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

これまでヘルパーT細胞の分化機構に関しては転写ネットワークによる制御機構に関する報告が多くなされてきたが、エピジェネティック制御による調節機構についての研究は端緒についたばかりである。本研究では、Tetによる末梢でのTreg/Th17分化制御機構について明らかとし、本研究がさらに発展すれば、免疫疾患、炎症性疾患やがんの新規治療法確立への応用が期待される。