Bisiaux Aurélie, Boussier Jeremy, Duffy Darragh, Quintana-Murci Lluis, Fontes Magnus, Albert Matthew L
INSERM U1223, Paris, France.
Laboratory of Dendritic Cell Immunobiology, Department of Immunology, Institut Pasteur, Paris, France.
Front Immunol. 2017 Jul 13;8:796. doi: 10.3389/fimmu.2017.00796. eCollection 2017.
Bacillus Calmette-Guérin (BCG) is used as a vaccine and diagnostic test for tuberculosis, as well as immunotherapy in the treatment of bladder cancer. While clinically useful, the response to mycobacterial stimulation is complex and the induced protein signature remains poorly defined. We characterized the cell types directly engaged by BCG, as well as the induced cytokine loops that transmit signal(s) to bystander cells. Standardized whole-blood stimulations and mechanistic studies on single and purified cell populations identified distinct patterns of activation in monocytes as compared to neutrophils and invariant lymphocyte populations. Deconvoluting the role of Toll-like receptor 2/4 and Dectin-1/2 in the inflammatory response to BCG, we revealed Dectin-1/2 as dominant in neutrophils as compared to monocytes, which equally engaged both pathways. Furthermore, we quantified the role of NF-κB and NADPH/reactive oxygen species (ROS)-dependent cytokines, which triggered a JAK1/2-dependent amplification loop and accounted for 40-50% of the induced response to BCG. In sum, this study provides new insight into the molecular and cellular pathways involved in the response to BCG, establishing the basis for a new generation of immunodiagnostic tools.
卡介苗（BCG）被用作结核病的疫苗和诊断测试，以及膀胱癌治疗中的免疫疗法。虽然在临床上有用，但对分枝杆菌刺激的反应很复杂，诱导的蛋白质特征仍不清楚。我们表征了直接与卡介苗相互作用的细胞类型，以及向旁观者细胞传递信号的诱导细胞因子环。对标准化全血刺激以及对单个和纯化细胞群体的机制研究表明，与中性粒细胞和恒定淋巴细胞群体相比，单核细胞具有不同的激活模式。通过剖析Toll样受体2/4和Dectin-1/2在对卡介苗炎症反应中的作用，我们发现与单核细胞相比，Dectin-1/2在中性粒细胞中占主导地位，而单核细胞同等程度地参与了这两条途径。此外，我们量化了NF-κB和NADPH/活性氧（ROS）依赖性细胞因子的作用，它们触发了JAK1/2依赖性放大环，并占卡介苗诱导反应的40-50%。总之，这项研究为卡介苗反应所涉及的分子和细胞途径提供了新的见解，为新一代免疫诊断工具奠定了基础。
