Immune regulation by sensing endogenous lipid composition changes via inhibitory C-type lectin receptor

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07623
• 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: Kumamoto University
• Principal Investigator: Motozono Chihiro 熊本大学, ヒトレトロウイルス学共同研究センター, 講師 (10642910)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 免疫受容体 / 抑制型受容体 / 結核菌

Outline of Final Research Achievements

Although the activating signals are balanced by inhibitory receptor-mediated signals, which maintains immune homeostasis, ligand recognitions and functions via inhibitory innate-receptors bearing ITIMs (Immunoreceptor tyrosine-based inhibitory motifs) remains unclear. To identify their endogenous ligands, we employed nuclear factor of activated T-cells (NFAT)-GFP reporter cells expressing chimeric inhibitory CLRs fused to CD3ζ and analyzed the reporter activity in response to various components. We identified the structure of their lipid ligands from plasma membrane and Mycobacteria. Mycobacteria infection experiment revealed that T cell recall responses were substantially enhanced in mice lacking the inhibitory receptor. These data indicate that blockade of the inhibitory receptor interaction and signaling potentiate cellular immunity against mycobacteria.

Free Research Field

感染免疫学

Academic Significance and Societal Importance of the Research Achievements

免疫応答は活性化シグナルとそれを制御する抑制性シグナルとの正負のバランスによって適切に調節されているが、抑制化シグナルを担っている抑制型免疫受容体の機能は未だ不明な点が多い。本研究では、抑制型受容体の内因性脂質リガンドならびに結核菌由来の脂質リガンド構造の同定に成功した。また結核菌感染動物モデルにおいて、野生型と比較して抑制型受容体欠損マウスでT細胞応答が増強されることが明らかになった。以上から、この抑制型受容体の認識を阻害することで免疫応答を増強させる新たな免疫チェックポイント阻害剤の可能性が示唆された。