Antibody-Fab and -Fc features promote Mycobacterium tuberculosis restriction. 

Patricia S. Grace, Joshua M. Peters, Jaimie Sixsmith, Richard Lu, Corinne Luedeman, Brooke A. Fenderson, Andrew Vickers, Matthew D. Slein, Edward B. Irvine, Tanya McKitrick, Mo-Hui Wei, Richard D. Cummings, Aaron Wallace, Lisa A. Cavacini, Alok Choudhary, Megan K. Proulx, Christopher Sundling, Gunilla Källenius, Rajko Reljic, Joel D. Ernst, Arturo Casadevall, Camille Locht, Abraham Pinter, Christopher M. Sasseti, Bryan D. Bryson, Sarah M. Fortune, Galit Alter

DOI:

Abstract: 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.