The role of DNA demethylase TET in T cell function and differentiation.

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K15198
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: Keio University
• Principal Investigator: NAKATSUKASA Hiroko 慶應義塾大学, 医学部(信濃町), 助教 (90749334)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Keywords: DNAメチル化 / 制御性T細胞 / エピジェネティクス / 自己免疫疾患 / 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 periphery. Furthermore, DKO phenotypes were abrogated by treatment of antibiotics, especially by metronidazole, or restriction of TCR repertoire, suggesting the contribution of gut microbiota as intestinal antigen. We also revealed the involvement of upstream region of Foxp3 gene as Tet target region to regulate Treg stability. Thus, Tet plays important roles in T cell differentiation and function.

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急速に研究が進み、転写ネットワークによるヘルパーT細胞の分化機構については非常に多くの報告がなされているが、エピジェネティックな制御による可塑性、安定性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DNA脱メチル化酵素TETがヘルパーT細胞分化の安定性と可塑性に関与することを明らかとしたが、今後さらに詳細な制御機構が解明されれば、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。