Laboratory of Immunoengineering, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, Netherlands.
Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, Eindhoven, Netherlands.
Elife. 2023 Jan 11;12:e83055. doi: 10.7554/eLife.83055.
Type I interferon (IFN-I)-mediated antiviral responses are central to host defense against viral infections. Crucial is the tight and well-orchestrated control of cellular decision-making leading to the production of IFN-Is. Innovative single-cell approaches revealed that the initiation of IFN-I production is limited to only fractions of 1-3% of the total population, both found in vitro, in vivo, and across cell types, which were thought to be stochastically regulated. To challenge this dogma, we addressed the influence of various stochastic and deterministic host-intrinsic factors on dictating early IFN-I responses, using a murine fibroblast reporter model. Epigenetic drugs influenced the percentage of responding cells. Next, with the classical Luria-Delbrück fluctuation test, we provided evidence for transient heritability driving responder fates, which was verified with mathematical modeling. Finally, while studying varying cell densities, we substantiated an important role for cell density in dictating responsiveness, similar to the phenomenon of quorum sensing. Together, this systems immunology approach opens up new avenues to progress the fundamental understanding on cellular decision-making during early IFN-I responses, which can be translated to other (immune) signaling systems.
I 型干扰素 (IFN-I) 介导的抗病毒反应是宿主防御病毒感染的核心。关键是要严格、协调地控制细胞决策，从而产生 IFN-Is。创新的单细胞方法表明， IFN-I 产生的起始仅局限于总群体的 1-3%，无论是在体外、体内还是在不同的细胞类型中，都被认为是随机调控的。为了挑战这一观点，我们使用了一种鼠成纤维细胞报告模型，研究了各种随机和确定性的宿主内在因素对早期 IFN-I 反应的影响。表观遗传药物影响了应答细胞的比例。接下来，通过经典的 Luria-Delbrück 波动试验，我们为驱动应答者命运的瞬时遗传提供了证据，这一证据通过数学建模得到了验证。最后，在研究不同的细胞密度时，我们证实了细胞密度在决定应答性方面的重要作用，类似于群体感应现象。总之，这种系统免疫学方法为深入了解早期 IFN-I 反应过程中的细胞决策开辟了新的途径，这可以转化为其他（免疫）信号转导系统。
