Fc-engineered antibodies leverage neutrophils to drive control ofMycobacterium tuberculosis

Novel vaccination and therapeutic strategies are urgently needed to mitigate the tuberculosis (TB) epidemic. While extensive efforts have focused on potentiating cell-mediated immunity to controlMycobacterium tuberculosis(Mtb) infection, less effort has been invested in exploiting the humoral immune system to combatMtb. Emerging data point to a role for antibodies in microbial control ofMtb, however the precise mechanism(s) of this control remain incompletely understood. Here we took an antibody Fc-engineering approach to determine whether Fc-modifications could improve the ability of antibodies to restrictMtb, and to define Fc-mediated mechanism(s) antibodies leverage for this restriction. Using an antibody specific to the capsular polysaccharide α-glucan, we engineer a panel of Fc variants to augment or dampen select antibody effector functions, rationally building antibodies with enhanced capacity to promoteMtbrestriction in a human whole blood model of infection. Surprisingly, restrictive Fc-engineered antibodies driveMtbcontrol in a neutrophil, not monocyte, dependent manner. Using single cell RNA sequencing, we show that restrictive antibodies promote neutrophil survival and expression of cell intrinsic antimicrobial programs. These data provide a roadmap for exploiting Fc-engineered antibodies as a novel class of TB therapeutics able to harness the protective functions of neutrophils to achieve disease control.