Antibody-Fab and -Fc features promote Mycobacterium tuberculosis restriction.
Grace, P. S.; Peters, J. M.; Sixsmith, J.; Lu, R.; Fenderson, B. A.; Vickers, A.; Slein, M. D.; Irvine, E. B.; McKitrick, T.; Wei, M.-H.; Cummings, R. D.; Wallace, A.; Cavacini, L.; Choudhary, A. K.; Proulx, M. K.; Sundling, C.; Källenius, G.; Reljic, R.; Ernst, J. D.; Casadevall, A.; Locht, C.; Pinter, A.; Sassetti, C. M.; Bryson, B. D.; Fortune, S. M.; Alter, G.
Show abstract
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is a leading cause of death by an infectious disease globally, with no efficacious vaccine. Antibodies are implicated in Mtb control, but the mechanisms of antibody action remain poorly understood. We assembled a library of TB monoclonal antibodies (mAb) and screened for the ability to restrict Mtb in mice, identifying protective antibodies targeting known and novel antigens. To dissect the mechanism of mAb-mediated Mtb restriction, we optimized a protective lipoarabinomannan-specific mAb through Fc-swapping. In vivo analysis of these Fc-variants revealed a critical 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 molecular circuitry within innate immune cell subpopulations, highlighting early activation of neutrophils as a key signature of mAb-mediated Mtb restriction. Therefore, improved 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.
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