Impact of HCMV-encoded FcγR antagonists on innate immune cell function

HCMV编码独特的大量免疫evasins，包括Fcγ结合糖蛋白gp 34（RL 11）、gp 68（UL 119 -118）和gp 95（RL 12）。我们证明，这些因子具有抑制IgG介导的效应子功能的能力，例如触发激活Fcγ受体FcγRIII/CD 16、FcγRII/CD 32和FcγRI/CD 64，前者通过自然杀伤（NK）细胞执行抗体依赖性细胞毒性（ADCC）。同时，HCMV感染诱导“适应性”NK细胞的发生和扩增，这在未感染个体中未观察到。“适应性”NK细胞不同于常规NK细胞，并且发挥特别有效的抗病毒效应子功能，例如ADCC。基于我们对分子作用模式以及gp 34和gp 68如何合作的发现，我们现在能够开发新的实验系统，该系统允许“适应性”NK细胞的Fcγ RIII依赖性扩增，并首次证明gp 34和gp 68的阻塞潜力。这种方法还使我们能够与P09合作研究针对gp 34和gp 68的天然抗体应答对体外和体内潜伏感染相对于HCMV疾病的条件下的“适应性”NK细胞扩增的影响。最后，将HCMV拮抗剂减弱FcγR免疫细胞的假设转移至CD 16 + γ δ T细胞，并在建立合适的体外培养条件后进行测试。结合通过Cryo-EM的gp 34和gp 68超微结构的分辨率，并应用一组新开发的识别gp 34和gp 68的单克隆抗体，我们设想了基于抗体的干预措施的新分子概念，可以允许靶向调节“适应性”NK细胞以及γ δ CDT细胞功能。

HCMV encodes a uniquely large arsenal of immunoevasins, including the Fcγ-binding glycoproteins gp34 (RL11), gp68 (UL119-118) and gp95 (RL12). We demonstrated that these factors share the ability to inhibit IgG-mediated effector functions such as triggering of the activating Fcγ receptors FcγRIII/CD16, FcγRII/CD32 and FcγRI/CD64, the former executing antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells. At the same time, HCMV infection induces the occurrence and expansion of "adaptive" NK cells, which are not observed in uninfected individuals. "Adaptive" NK cells differ from conventional NK cells and exert particularly effective antiviral effector functions, such as ADCC. Based on our findings on the molecular mode of action and how gp34 and gp68 cooperate, we are now in the position to develop new experimental systems, which allow FcγRIII-dependent expansion of “adaptive” NK cells in vitro and demonstrate for the first time the obstructive potential of gp34 and gp68. This approach enables us also to investigate in cooperation with P09 the impact of natural antibody responses against gp34 and gp68 on ”adaptive” NK cell expansion in vitro and under conditions of latent infection vs. HCMV disease in vivo. Finally, the hypothesis of FcγR immune cell attenuation by HCMV antagonists will be transferred to CD16+ gamma delta T cells and tested after the establishment of suitable culture conditions in vitro. In conjunction with the resolution of the gp34 and gp68 ultrastructure via Cryo-EM and applying a panel of newly developed monoclonal antibodies recognizing gp34 and gp68, we envisage new molecular concepts for antibody-based interventions that could allow the targeted modulation of "adaptive" NK as well as gamma deltaT cell functions.