Analysis of novel molecular mechanism of iNKT cell differentiation based on the discovery of mice deficient in iNKT cells

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07624
• 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: Osaka University
• Principal Investigator: ISHIKAWA Eri 大阪大学, 微生物病研究所, 助教 (20546478)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: iNKT細胞分化 / セリンスレオニンキナーゼ / TCRシグナル

Outline of Final Research Achievements

We established CD4-Cre-mediated T cell specific PKD-deficient mice and found that iNKT cells were almost absent in the mice. On the basis of this finding, we tried to reveal the novel molecular mechanism of iNKT cell development.
Expression of a transcription factor PLZF, which is necessary for the specification of iNKT cells, was decreased in PKD-deficient cells. Introduction of PLZF transgene in PKD-deficient mice restored the generation of iNKT cells, suggesting that PKD contributes to the induction of PLZF to regulate iNKT cell development. To investigate the molecular link between PKD and PLZF, we searched for PKD substrates by phosphoproteomics and identified a candidate transcription factor. This factor was associated with and phosphorylated by PKD upon TCR stimulation. These results unveiled the novel role of PKD in iNKT development through the regulation of nuclear factors.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

iNKT細胞の分化には転写因子PLZFの発現が必須であることが知られているが、TCRからPLZF発現に至るシグナル経路の詳細は未だ明らかになっていない。また、PKDは細胞質のみでなく核にも局在することが知られているが、核における機能に関しては未だ不明な点が多い。
本研究で得られた成果は、核におけるPKDの重要性を明らかにすると共に、PKDがTCR下流で転写因子のリン酸化を介してPLZFの発現を誘導しiNKT細胞分化を制御するという、iNKT細胞分化の新たな分子機構の存在を強く示唆するものである。