Spatial localization of CD16a at the human NK cell ADCC lytic synapse

Patrick Ross, Hijab Fatima, Daniel P Leaman, Jessica Matthias, Kathryn Spencer, Michael B Zwick, Scott C Henderson, Emily M. Mace, Charles Daniel Murin
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Abstract

Natural Killer (NK) cells utilize effector functions, including antibody-dependent cellular cytotoxicity (ADCC), for the clearance of viral infection and cellular malignancies. NK cell ADCC is mediated by Fc𝛾RIIIa (CD16a) binding to the fragment crystallizable (Fc) region of immunoglobulin G (IgG) within immune complexes on a target cell surface. While antibody-induced clustering of CD16a is thought to drive ADCC, the molecular basis for this activity has not been fully described. Here we use MINFLUX nanoscopy to map the spatial distribution of stoichiometrically labeled CD16a across the NK cell membrane, revealing the presence of pairs of CD16a molecules with intra-doublet distance of approximately 17 nm. NK cells activated on supported lipid bilayers by Trastuzumab results in an increase of synaptic regions with greater CD16a density. Our results provide the highest spatial resolution yet described for CD16a imaging, offering new insight into how CD16a organization could influence ADCC activity, for example through self-association or with binding partners influencing the degree of ADCC signaling. MINFLUX holds great promise to further unravel the molecular details driving CD16a-based activation of NK cells.
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CD16a 在人类 NK 细胞 ADCC 溶解突触处的空间定位
自然杀伤(NK)细胞利用效应器功能(包括抗体依赖性细胞毒性(ADCC))清除病毒感染和细胞恶性肿瘤。NK 细胞的 ADCC 是由 Fc𝛾RIIIa (CD16a) 与靶细胞表面免疫复合物中免疫球蛋白 G (IgG) 的可结晶片段 (Fc) 区域结合介导的。虽然抗体诱导的 CD16a 聚集被认为是 ADCC 的驱动力,但这种活性的分子基础尚未得到充分描述。在这里,我们使用 MINFLUX 纳米透视技术绘制了 NK 细胞膜上按比例标记的 CD16a 的空间分布图,揭示了成对的 CD16a 分子的存在,其双顶体内部距离约为 17 纳米。曲妥珠单抗激活了支撑脂质双层膜上的NK细胞,导致CD16a密度更高的突触区域增加。我们的研究结果提供了迄今为止 CD16a 成像的最高空间分辨率,让我们对 CD16a 组织如何影响 ADCC 活性有了新的认识,例如通过自我结合或与影响 ADCC 信号传导程度的结合伙伴结合。MINFLUX 很有希望进一步揭示驱动基于 CD16a 的 NK 细胞活化的分子细节。
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