DNAM-1 regulates Foxp3 expression in regulatory T cells by interfering with TIGIT under inflammatory conditions

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K16599
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: University of Tsukuba
• Principal Investigator: Sato Kazuki 筑波大学, 生存ダイナミクス研究センター, 助教 (10802621)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: 免疫寛容 / 制御性T細胞 / 移植片対宿主病

Outline of Final Research Achievements

Immune tolerance is essential to prevent autoimmune responses, but it often needs to be limited for proper immune response. Regulatory T (Treg) cells play a crucial role in immune tolerance; however, their immune-suppressive function is restricted under inflammatory conditions. Here, we show that the activated immune receptor DNAM-1 limits Treg cell function regardless of DNAM-1 mediated intracellular signaling. We found that DNAM-1 competes with T cell immunoreceptor with Ig and ITIM domains (TIGIT) in binding to a common ligand. DNAM-1 deficiency enhances TIGIT signaling, thus resulting in the Treg cell function’s maintenance under inflammatory conditions. These results suggest that the DNAM-1 and TIGIT balance orchestrate Treg cell function for optimal immune reaction.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

移植片対宿主病(GVHD)は造血器悪性腫瘍や再生不良性貧血に対する治療として行われる同種造血幹細胞移植における最も重篤な合併症であり、生命予後にも直接影響するため、優れた治療法の開発が急務である。
本研究は、免疫抑制機能を担う制御性T細胞(Treg)に着目し、Treg細胞上に発現する免疫受容体DNAM-1を阻害することでTreg細胞の機能を飛躍的に増強させることを見出し、GVHD病態を軽快させる分子機構を解明した。以上の結果より、DNAM-1を標的としたGVHD の新たな治療法の開発が期待される。