Antibody-Fab and -Fc features promote Mycobacterium tuberculosis restriction

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), a leading cause of death by an infectious disease globally, has no efficacious vaccine. Antibodies are implicated in Mtb control, but the mechanisms of action remain poorly understood. We assembled a library of monoclonal antibodies (mAb) and screened for Mtb-restrictive activity in mice, identifying protective antibodies targeting diverse antigens. To dissect the mechanism of mAb-mediated Mtb 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 Mtb restriction. Restrictive Fc-variants altered distribution of Mtb across innate immune cells. Single-cell transcriptomics highlighted distinctly activated pathways within innate immune cell subpopulations, highlighting early activation of neutrophils as a key signature of mAb-mediated Mtb restriction. Therefore, antibody-mediated restriction of Mtb is associated with reorganization of the tissue-level immune response to infection and depends on the collaboration of antibody Fab and Fc.