Page Audrey, Delles Marie, Nègre Didier, Costa Caroline, Fusil Floriane, Cosset François-Loïc
CIRI - Centre International de Recherche en Infectiologie, University Lyon, Université Claude Bernard Lyon 1, Inserm, U1111, CNRS, UMR5308, ENS Lyon, 46 Allée d'Italie, 69007 Lyon, France.
Mol Ther Nucleic Acids. 2023 Jun 3;33:1-14. doi: 10.1016/j.omtn.2023.05.024. eCollection 2023 Sep 12.
The expansion of genetic engineering has brought a new dimension for synthetic immunology. Immune cells are perfect candidates because of their ability to patrol the body, interact with many cell types, proliferate upon activation, and differentiate in memory cells. This study aimed at implementing a new synthetic circuit in B cells, allowing the expression of therapeutic molecules in a temporally and spatially restricted manner that is induced by the presence of specific antigens. This should enhance endogenous B cell functions in terms of recognition and effector properties. We developed a synthetic circuit encoding a sensor (a membrane-anchored B cell receptor targeting a model antigen), a transducer (a minimal promoter induced by the activated sensor), and effector molecules. We isolated a 734-bp-long fragment of the NR4A1 promoter, specifically activated by the sensor signaling cascade in a fully reversible manner. We demonstrate full antigen-specific circuit activation as its recognition by the sensor induced the activation of the NR4A1 promoter and the expression of the effector. Overall, such novel synthetic circuits offer huge possibilities for the treatment of many pathologies, as they are completely programmable; thus, the signal-specific sensors and effector molecules can be adapted to each disease.
基因工程的扩展为合成免疫学带来了新的维度。免疫细胞是理想的选择，因为它们能够在体内巡逻、与多种细胞类型相互作用、激活后增殖并分化为记忆细胞。本研究旨在在B细胞中构建一种新的合成回路，使治疗性分子能够在特定抗原存在时以时空受限的方式表达。这应能在识别和效应特性方面增强内源性B细胞功能。我们开发了一种合成回路，其编码一个传感器（靶向模型抗原的膜锚定B细胞受体）、一个转导器（由激活的传感器诱导的最小启动子）和效应分子。我们分离出了NR4A1启动子的一个734 bp长的片段，该片段在传感器信号级联反应中以完全可逆的方式被特异性激活。我们证明了完全的抗原特异性回路激活，因为传感器对其识别诱导了NR4A1启动子的激活和效应分子的表达。总体而言，这种新型合成回路为许多疾病的治疗提供了巨大的可能性，因为它们是完全可编程的；因此，信号特异性传感器和效应分子可以针对每种疾病进行调整。
