Hoepel Willianne, Allahverdiyeva Sona, Harbiye Haneen, de Taeye Steven W, van der Ham Alwin J, de Boer Leonie, Zaat Sebastiaan A J, van Weeghel Michel, Baeten Dominique L P, Houtkooper Riekelt H, Everts Bart, Vidarsson Gestur, den Dunnen Jeroen
Amsterdam Rheumatology and Immunology Center, Department of Rheumatology and Clinical Immunology, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
J Immunol. 2020 Dec 15;205(12):3400-3407. doi: 10.4049/jimmunol.2000263. Epub 2020 Nov 13.
IgG Abs are crucial for various immune functions, including neutralization, phagocytosis, and Ab-dependent cellular cytotoxicity. In this study, we identified another function of IgG by showing that IgG immune complexes elicit distinct cytokine profiles by human myeloid immune cells, which are dependent on FcγR activation by the different IgG subclasses. Using monoclonal IgG subclasses with identical Ag specificity, our data demonstrate that the production of Th17-inducing cytokines, such as TNF, IL-1β, and IL-23, is particularly dependent on IgG2, whereas type I IFN responses are controlled by IgG3, and IgG1 is able to regulate both. In addition, we identified that subclass-specific cytokine production is orchestrated at the posttranscriptional level through distinct glycolytic reprogramming of human myeloid immune cells. Combined, these data identify that IgG subclasses provide pathogen- and cell type-specific immunity through differential metabolic reprogramming by FcγRs. These findings may be relevant for future design of Ab-related therapies in the context of infectious diseases, chronic inflammation, and cancer.
IgG抗体对于多种免疫功能至关重要，包括中和作用、吞噬作用和抗体依赖性细胞毒性作用。在本研究中，我们通过证明IgG免疫复合物可由人类髓系免疫细胞引发不同的细胞因子谱，从而确定了IgG的另一种功能，这一过程依赖于不同IgG亚类对FcγR的激活。使用具有相同抗原特异性的单克隆IgG亚类，我们的数据表明，诱导Th17的细胞因子（如TNF、IL-1β和IL-23）的产生特别依赖于IgG2，而I型干扰素反应则由IgG3控制，IgG1能够调节两者。此外，我们发现亚类特异性细胞因子的产生是在转录后水平通过人类髓系免疫细胞独特的糖酵解重编程来协调的。综合来看，这些数据表明IgG亚类通过FcγR的差异代谢重编程提供病原体和细胞类型特异性免疫。这些发现可能与未来在传染病、慢性炎症和癌症背景下设计抗体相关疗法有关。
