Department of Surgery, Duke University, Durham, NC, United States.
Duke Human Vaccine Institute, Durham, NC, United States.
Front Immunol. 2023 Dec 6;14:1260377. doi: 10.3389/fimmu.2023.1260377. eCollection 2023.
Rhesus macaques (RMs) are a common pre-clinical model used to test HIV vaccine efficacy and passive immunization strategies. Yet, it remains unclear to what extent the Fc-Fc receptor (FcR) interactions impacting antiviral activities of antibodies in RMs recapitulate those in humans. Here, we evaluated the FcR-related functionality of natural killer cells (NKs) from peripheral blood of uninfected humans and RMs to identify intra- and inter-species variation. NKs were screened for FcγRIIIa (human) and FcγRIII (RM) genotypes (FcγRIII(a)), receptor signaling, and antibody-dependent cellular cytotoxicity (ADCC), the latter mediated by a cocktail of monoclonal IgG1 antibodies with human or RM Fc. FcγRIII(a) genetic polymorphisms alone did not explain differences in NK effector functionality in either species cohort. Using the same parameters, hierarchical clustering separated each species into two clusters. Importantly, in principal components analyses, ADCC magnitude, NK contribution to ADCC, FcγRIII(a) cell-surface expression, and frequency of phosphorylated CD3ζ NK cells all contributed similarly to the first principal component within each species, demonstrating the importance of measuring multiple facets of NK cell function. Although ADCC potency was similar between species, we detected significant differences in frequencies of NK cells and pCD3ζ+ cells, level of cell-surface FcγRIII(a) expression, and NK-mediated ADCC (P<0.001), indicating that a combination of Fc-FcR parameters contribute to overall inter-species functional differences. These data strongly support the importance of multi-parameter analyses of Fc-FcR NK-mediated functions when evaluating efficacy of passive and active immunizations in pre- and clinical trials and identifying correlates of protection. The results also suggest that pre-screening animals for multiple FcR-mediated NK function would ensure even distribution of animals among treatment groups in future preclinical trials.
食蟹猴（RMs）是一种常用于测试 HIV 疫苗功效和被动免疫策略的常见临床前模型。然而，目前尚不清楚影响抗体抗病毒活性的 Fc-Fc 受体（FcR）相互作用在多大程度上在 RMs 中重现于人类。在这里，我们评估了来自未感染人类和 RMs 外周血的自然杀伤细胞（NKs）的 FcR 相关功能，以确定种内和种间的差异。筛选 NK 细胞的 FcγRIIIa（人类）和 FcγRIII（RM）基因型（FcγRIII(a)）、受体信号传导和抗体依赖性细胞毒性（ADCC），后者由一组与人或 RM Fc 结合的单克隆 IgG1 抗体介导。FcγRIII(a)遗传多态性本身并不能解释两种物种群体中 NK 效应功能的差异。使用相同的参数，层次聚类将每个物种分为两个簇。重要的是，在主成分分析中，ADCC 幅度、NK 对 ADCC 的贡献、FcγRIII(a)细胞表面表达和磷酸化 CD3ζ NK 细胞的频率都在每个物种的第一主成分中做出了类似的贡献，这表明测量 NK 细胞功能的多个方面非常重要。尽管两种物种之间的 ADCC 效力相似，但我们检测到 NK 细胞和 pCD3ζ+细胞的频率、FcγRIII(a)表面表达水平以及 NK 介导的 ADCC 存在显著差异（P<0.001），表明 Fc-FcR 参数的组合有助于整体种间功能差异。这些数据强烈支持在评估临床前和临床试验中被动和主动免疫的疗效以及确定保护相关性时，对 Fc-FcR NK 介导的功能进行多参数分析的重要性。结果还表明，在未来的临床前试验中，对多种 FcR 介导的 NK 功能进行预筛选可以确保动物在治疗组中的均匀分布。
