Grace Patricia S, Peters Joshua M, Sixsmith Jaimie, Lu Richard, Irvine Edward B, Luedeman Corinne, Fenderson Brooke A, Vickers Andrew, Slein Matthew D, McKitrick Tanya, Wei Mo-Hui, Cummings Richard D, Wallace Aaron, Cavacini Lisa A, Choudhary Alok, Proulx Megan K, Sundling Christopher, Källenius Gunilla, Reljic Rajko, Ernst Joel D, Casadevall Arturo, Locht Camille, Pinter Abraham, Sassetti Christopher M, Bryson Bryan D, Fortune Sarah M, Alter Galit
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
Immunity. 2025 Jun 10;58(6):1586-1597.e5. doi: 10.1016/j.immuni.2025.05.004. Epub 2025 May 30.
Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), a leading cause of death by an infectious disease globally, has no efficacious vaccine. Antibodies are implicated in M. tuberculosis control, but the mechanisms of action remain poorly understood. We assembled a library of monoclonal antibodies (mAb) and screened for M. tuberculosis-restrictive activity in mice, identifying protective antibodies targeting diverse antigens. To dissect the mechanism of mAb-mediated M. tuberculosis restriction, we optimized a protective lipoarabinomannan-specific mAb, generating Fc variants. In vivo analysis of these Fc variants revealed a role for Fc-effector function in M. tuberculosis restriction. Restrictive Fc variants altered distribution of M. tuberculosis across innate immune cells. Single-cell transcriptomics highlighted distinctly activated pathways within innate immune cell subpopulations, identifying early activation of neutrophils as a key signature of mAb-mediated M. tuberculosis restriction. Therefore, antibody-mediated restriction of M. tuberculosis is associated with reorganization of the tissue-level immune response to infection and depends on the collaboration of antibody Fab and Fc.
结核分枝杆菌是结核病（TB）的病原体，结核病是全球传染病致死的主要原因之一，目前尚无有效的疫苗。抗体参与了对结核分枝杆菌的控制，但其作用机制仍知之甚少。我们构建了一个单克隆抗体（mAb）文库，并在小鼠中筛选对结核分枝杆菌有抑制活性的抗体，鉴定出了针对多种抗原的保护性抗体。为了剖析单克隆抗体介导的结核分枝杆菌抑制机制，我们优化了一种针对脂阿拉伯甘露聚糖的保护性单克隆抗体，生成了Fc变体。对这些Fc变体的体内分析揭示了Fc效应功能在结核分枝杆菌抑制中的作用。具有抑制作用的Fc变体改变了结核分枝杆菌在天然免疫细胞中的分布。单细胞转录组学突出了天然免疫细胞亚群内明显激活的信号通路，确定中性粒细胞的早期激活是单克隆抗体介导的结核分枝杆菌抑制的关键特征。因此，抗体介导的结核分枝杆菌抑制与感染的组织水平免疫反应的重组有关，并且依赖于抗体Fab和Fc的协同作用。
