ESAT-6 and CFP-10 reactive IgG in patients with tuberculosis inhibits intracellular bacteria

Perspectives beyond the CD4 T cell interferon (IFN)-γ paradigm are needed to understand immunity in tuberculosis (TB). Growing data in patients across a spectrum of TB highlight that changes in antibody Fc domain glycosylation and Fc effector functions correlate with disease and impact Mycobacterium tuberculosis (Mtb) infection. How antigen-specific antibodies within polyclonal responses affect bacteria is less clear. This study examines antibodies targeting ESAT-6 and CFP-10, Mtb virulence proteins essential for pathogenesis. Data from patients with TB show that polyclonal immunoglobulin (Ig)G reactive to ESAT-6 and CFP-10 diverges from other Mtb and non-Mtb antigens with enhanced sialylation, afucosylation, natural killer cell-mediated cellular cytotoxicity, and association with anti-microbial activity against intracellular Mtb. Monoclonal antibody studies show that intracellular Mtb inhibition is dependent on antigen binding, N-linked glycans, and Fc-Fc receptor (FcR) engagement. These findings demonstrate that some antibodies in patients inhibit Mtb in its quintessential intracellular niche, opening avenues to appreciate how humoral immunity impacts TB.