Abstract
ABSTRACTNovel 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.
Publisher
Cold Spring Harbor Laboratory
Cited by
2 articles.
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