共抑制分子TIGIT介导NK细胞肝脏免疫耐受的分子机制

负相共刺激因子CTLA-4和PD-1在肿瘤免疫治疗中展现了诱人前景。2009年发现了第一个NK细胞负相共刺激因子TIGIT，本研究拟率先研究TIGIT对富含NK细胞的肝脏免疫耐受的作用。本研究小组已成功研制小鼠可溶性TIGIT、TIGIT- mAb、TIGIT-FC、TIGIT表达载体和TIGIT-shRNA载体并获得TIGIT-KO鼠，将进一步研究NK细胞共刺激分子CD226与TIGIT共同决定NK细胞活化与去活化的平衡机制、肝脏各种细胞通过表达TIGIT配体CD155以诱发NK细胞耐受的Cross-Talk机制、TIGIT诱发NK细胞耐受的主要信号通路、应用本实验室创建的多种NK介导的肝脏免疫损伤模型深入验证这些细胞与分子机制并探讨靶向TIGIT以治疗肝脏免疫相关疾病的可能性。

Negative co-stimulatory molecules CTLA-4 and PD-1 have shown promising future in tumor immmunotherapy. TIGIT was the first negative co-stimulatory molecule found on Natural Killer cells in 2009. In the current research project, we aim to study the role of TIGIT in the immunotolerance of the liver, an organ enriched with Natural Killer cells. We have already generated soluble TIGIT, TIGIT-mAb, TIGIT-FC, TIGIT-expressing vectors, TIGIT-shRNA vectors, and also TIGIT-KO mice. We are going to further investigate the mechanisms of how the co-stimulatory molecules CD226 and TIGIT determining the balance between NK cell activation and de-activation, the possible cross-talk mechanisms underlying NK cell immunotolerance induced by expressing TIGIT receptor CD155, the major signaling pathways through which NK cell immunotolerance can be induced; along with the use of variety of NK cell-mediated liver injury models to further verify these cellular and molecular mechanisms, and to explore the possibilities of targeting TIGIT in order to cure various liver diseases.