Haas Tobias, Heidegger Simon, Wintges Alexander, Bscheider Michael, Bek Sarah, Fischer Julius C, Eisenkolb Gabriel, Schmickl Martina, Spoerl Silvia, Peschel Christian, Poeck Hendrik, Ruland Jürgen
III. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
Eur J Immunol. 2017 May;47(5):872-879. doi: 10.1002/eji.201646775. Epub 2017 Apr 10.
Activation of the C-type lectin receptor Dectin-1 by β-glucans triggers multiple signals within DCs that result in activation of innate immunity. While these mechanisms can potently prime CD8 cytotoxic T-cell (CTL) responses without additional adjuvants, the Dectin-1 effector pathways that control CTL induction remain unclear. Here we demonstrate that Dectin-1-induced CTL cross-priming in mice does not require inflammasome activation but strictly depends on the adapter protein Card9 in vitro. In vivo, Dectin-1-mediated Card9 activation after vaccination drives both expansion and activation of Ag-specific CTLs, resulting in long-lasting CTL responses that are sufficient to protect mice from tumor challenge. This Dectin-1-induced antitumor immune response was independent of NK cell function and completely abrogated in Card9-deficient mice. Thus, our results demonstrate that Dectin-1-triggered Card9 signaling but not inflammasome activation can potently cross-prime Ag-specific CTLs, suggesting that this pathway would be a candidate for immunotherapy and vaccine development.
β-葡聚糖激活C型凝集素受体Dectin-1会在树突状细胞（DC）内触发多种信号，从而激活先天免疫。虽然这些机制无需额外佐剂就能有效启动CD8细胞毒性T细胞（CTL）反应，但控制CTL诱导的Dectin-1效应途径仍不清楚。在此，我们证明，在小鼠中，Dectin-1诱导的CTL交叉启动不需要炎性小体激活，但在体外严格依赖衔接蛋白Card9。在体内，疫苗接种后Dectin-1介导的Card9激活驱动了抗原特异性CTL的扩增和激活，产生了持久的CTL反应，足以保护小鼠免受肿瘤攻击。这种Dectin-1诱导的抗肿瘤免疫反应独立于自然杀伤细胞功能，在Card9缺陷小鼠中完全消除。因此，我们的结果表明，Dectin-1触发的Card9信号传导而非炎性小体激活能够有效交叉启动抗原特异性CTL，这表明该途径可能是免疫治疗和疫苗开发的一个候选途径。
