炎症体
CD8型
T细胞
细胞生物学
细胞毒性T细胞
免疫系统
免疫检查点
炎症
免疫
封锁
生物
免疫学
获得性免疫系统
效应器
癌症研究
化学
免疫疗法
受体
体外
生物化学
作者
Karen O. Dixon,Marcin Tabaka,M. Schramm,Sheng Xiao,Rui Tang,Danielle Dionne,Ana C. Anderson,Orit Rozenblatt-Rosen,Aviv Regev,Vijay K. Kuchroo
出处
期刊:Nature
[Springer Nature]
日期:2021-06-09
卷期号:595 (7865): 101-106
被引量:172
标识
DOI:10.1038/s41586-021-03626-9
摘要
T cell immunoglobulin and mucin-containing molecule 3 (TIM-3), first identified as a molecule expressed on interferon-γ producing T cells1, is emerging as an important immune-checkpoint molecule, with therapeutic blockade of TIM-3 being investigated in multiple human malignancies. Expression of TIM-3 on CD8+ T cells in the tumour microenvironment is considered a cardinal sign of T cell dysfunction; however, TIM-3 is also expressed on several other types of immune cell, confounding interpretation of results following blockade using anti-TIM-3 monoclonal antibodies. Here, using conditional knockouts of TIM-3 together with single-cell RNA sequencing, we demonstrate the singular importance of TIM-3 on dendritic cells (DCs), whereby loss of TIM-3 on DCs-but not on CD4+ or CD8+ T cells-promotes strong anti-tumour immunity. Loss of TIM-3 prevented DCs from expressing a regulatory program and facilitated the maintenance of CD8+ effector and stem-like T cells. Conditional deletion of TIM-3 in DCs led to increased accumulation of reactive oxygen species resulting in NLRP3 inflammasome activation. Inhibition of inflammasome activation, or downstream effector cytokines interleukin-1β (IL-1β) and IL-18, completely abrogated the protective anti-tumour immunity observed with TIM-3 deletion in DCs. Together, our findings reveal an important role for TIM-3 in regulating DC function and underscore the potential of TIM-3 blockade in promoting anti-tumour immunity by regulating inflammasome activation.
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