Institute of Biomedical Sciences, Shanxi University, Xiaodian District, Taiyuan City, Shanxi Province 030006, China.
Department of Dermatology, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
J Immunol. 2019 Apr 1;202(7):2057-2068. doi: 10.4049/jimmunol.1801449. Epub 2019 Feb 15.
CD160 is highly expressed by NK cells and is associated with cytolytic effector activity. Herpes virus entry mediator (HVEM) activates NK cells for cytokine production and cytolytic function via CD160. Fc-fusions are a well-established class of therapeutics, where the Fc domain provides additional biological and pharmacological properties to the fusion protein including enhanced serum and interaction with Fc receptor-expressing immune cells. We evaluated the specific function of HVEM in regulating CD160-mediated NK cell effector function by generating a fusion of the HVEM extracellular domain with human IgG1 Fc bearing CD16-binding mutations (Fc*) resulting in HVEM-(Fc*). HVEM-(Fc*) displayed reduced binding to the Fc receptor CD16 (i.e., Fc-disabled HVEM), which limited Fc receptor-induced responses. HVEM-(Fc*) functional activity was compared with HVEM-Fc containing the wild type human IgG1 Fc. HVEM-(Fc*) treatment of NK cells and PBMCs caused greater IFN-γ production, enhanced cytotoxicity, reduced NK fratricide, and no change in CD16 expression on human NK cells compared with HVEM-Fc. HVEM-(Fc*) treatment of monocytes or PBMCs enhanced the expression level of CD80, CD83, and CD40 expression on monocytes. HVEM-(Fc*)-enhanced NK cell activation and cytotoxicity were promoted via cross-talk between NK cells and monocytes that was driven by cell-cell contact. In this study, we have shown that soluble Fc-disabled HVEM-(Fc*) augments NK cell activation, IFN-γ production, and cytotoxicity of NK cells without inducing NK cell fratricide by promoting cross-talk between NK cells and monocytes without Fc receptor-induced effects. Soluble Fc-disabled HVEM-(Fc*) may be considered as a research and potentially therapeutic reagent for modulating immune responses via sole activation of HVEM receptors.
CD160 在 NK 细胞上高度表达，并与细胞溶解效应活性相关。疱疹病毒进入介体 (HVEM) 通过 CD160 激活 NK 细胞以产生细胞因子和细胞溶解功能。Fc 融合是一类成熟的治疗药物，其中 Fc 结构域为融合蛋白提供了额外的生物学和药理学特性，包括增强血清稳定性和与表达 Fc 受体的免疫细胞相互作用。我们通过生成 HVEM 细胞外结构域与人 IgG1 Fc 的融合来评估 HVEM 在调节 CD160 介导的 NK 细胞效应功能中的特定作用，该融合体带有 CD16 结合突变（Fc*），导致 HVEM-（Fc*）。HVEM-（Fc*）与 Fc 受体 CD16 的结合减少（即 Fc 失活的 HVEM），从而限制了 Fc 受体诱导的反应。HVEM-（Fc*）的功能活性与含有野生型人 IgG1 Fc 的 HVEM-Fc 进行了比较。与 HVEM-Fc 相比，HVEM-（Fc*）处理 NK 细胞和 PBMC 可导致 IFN-γ 产生增加、细胞毒性增强、NK 细胞自噬减少，而对人 NK 细胞上 CD16 的表达无变化。与 HVEM-Fc 相比，HVEM-（Fc*）处理单核细胞或 PBMC 可增强单核细胞上 CD80、CD83 和 CD40 的表达水平。HVEM-（Fc*）通过 NK 细胞和单核细胞之间的细胞间接触促进的相互作用增强了 NK 细胞的激活和细胞毒性。在这项研究中，我们表明可溶性 Fc 失活的 HVEM-（Fc*）通过促进 NK 细胞和单核细胞之间的相互作用来增强 NK 细胞的激活、IFN-γ 产生和 NK 细胞的细胞毒性，而不会通过诱导 NK 细胞自噬来诱导 NK 细胞自噬。Fc 失活的 HVEM-（Fc*）可能被认为是一种研究试剂，并且具有通过单独激活 HVEM 受体来调节免疫应答的潜力。
