Humans have four IgG antibody subclasses that selectively or differentially engage immune effector molecules to protect against infections. Although IgG1 has been studied in detail and is the subclass of most approved antibody therapeutics, increasing evidence indicates that IgG3 is associated with enhanced protection against pathogens. Here, we report that IgG3 has superior capacity to mediate intracellular antiviral immunity compared with the other subclasses due to its uniquely extended and flexible hinge region, which facilitates improved recruitment of the cytosolic Fc receptor TRIM21, independently of Fc binding affinity. TRIM21 may also synergize with complement C1/C4-mediated lysosomal degradation via capsid inactivation. We demonstrate that this process is potentiated by IgG3 in a hinge-dependent manner. Our findings reveal differences in how the four IgG subclasses mediate intracellular immunity, knowledge that may guide IgG subclass selection and engineering of antiviral antibodies for prophylaxis and therapy.

中文翻译：

---

有效的 TRIM21 和补体依赖性细胞内抗病毒免疫需要 IgG3 铰链

人类有四种 IgG 抗体亚类，它们选择性或差异地结合免疫效应分子以防止感染。尽管 IgG1 已被详细研究并且是大多数批准的抗体疗法的子类，但越来越多的证据表明 IgG3 与增强的病原体保护有关。在这里，我们报告说，由于 IgG3 具有独特的延伸和灵活的铰链区，因此与其他亚类相比，它具有更好的介导细胞内抗病毒免疫的能力，这有助于改善细胞溶质 Fc 受体 TRIM21 的募集，而与 Fc 结合亲和力无关。TRIM21 还可以通过衣壳失活与补体 C1/C4 介导的溶酶体降解协同作用。我们证明 IgG3 以依赖于铰链的方式加强了这一过程。