Mounting evidence indicates that antibodies can contribute towards control of tuberculosis (TB). However, the underlying mechanisms of humoral immune protection and whether antibodies can be exploited in therapeutic strategies to combat TB are relatively understudied. Here we engineered the receptor-binding Fc (fragment crystallizable) region of an antibody recognizing the Mycobacterium tuberculosis (Mtb) capsule, to define antibody Fc-mediated mechanism(s) of Mtb restriction. We generated 52 Fc variants that either promote or inhibit specific antibody effector functions, rationally building antibodies with enhanced capacity to promote Mtb restriction in a human whole-blood model of infection. While there is likely no singular Fc profile that universally drives control of Mtb, here we found that several Fc-engineered antibodies drove Mtb restriction in a neutrophil-dependent manner. Single-cell RNA sequencing analysis showed that a restrictive Fc-engineered antibody promoted neutrophil survival and expression of cell-intrinsic antimicrobial programs. These data show the potential of Fc-engineered antibodies as therapeutics able to harness the protective functions of neutrophils to promote control of TB.

越来越多的证据表明抗体有助于控制结核病 (TB)。然而，体液免疫保护的基本机制以及抗体是否可以用于对抗结核病的治疗策略的研究相对不足。在这里，我们设计了识别结核分枝杆菌( Mtb ) 荚膜的抗体的受体结合 Fc（可结晶片段）区域，以定义抗体 Fc 介导的Mtb限制机制。我们生成了 52 个 Fc 变体，它们可以促进或抑制特定的抗体效应器功能，合理地构建具有增强能力的抗体，以在人类全血感染模型中促进Mtb限制。虽然可能没有单一的 Fc 配置文件普遍驱动Mtb的控制，但在这里我们发现几种 Fc 工程抗体以中性粒细胞依赖性方式驱动Mtb限制。单细胞 RNA 测序分析表明，限制性 Fc 工程抗体可促进中性粒细胞存活和细胞固有抗菌程序的表达。这些数据显示了 Fc 工程抗体作为治疗剂的潜力，能够利用中性粒细胞的保护功能来促进结核病的控制。