Antigen-Specific Antibody Glycosylation Is Regulated via Vaccination

Antibody effector functions, such as antibody-dependent cellular cytotoxicity, complement deposition, and antibody-dependent phagocytosis, play a critical role in immunity against multiple pathogens, particularly in the absence of neutralizing activity. Two modifications to the IgG constant domain (Fc domain) regulate antibody functionality: changes in antibody subclass and changes in a single N-linked glycan located in the CH2 domain of the IgG Fc. Together, these modifications provide a specific set of instructions to the innate immune system to direct the elimination of antibody-bound antigens. While it is clear that subclass selection is actively regulated during the course of natural infection, it is unclear whether antibody glycosylation can be tuned, in a signal-specific or pathogen-specific manner. Here, we show that antibody glycosylation is determined in an antigen- and pathogen-specific manner during HIV infection. Moreover, while dramatic differences exist in bulk IgG glycosylation among individuals in distinct geographical locations, immunization is able to overcome these differences and elicit antigen-specific antibodies with similar antibody glycosylation patterns. Additionally, distinct vaccine regimens induced different antigen-specific IgG glycosylation profiles, suggesting that antibody glycosylation is not only programmable but can be manipulated via the delivery of distinct inflammatory signals during B cell priming. These data strongly suggest that the immune system naturally drives antibody glycosylation in an antigen-specific manner and highlights a promising means by which next-generation therapeutics and vaccines can harness the antiviral activity of the innate immune system via directed alterations in antibody glycosylation in vivo. Author Summary: Accumulating evidence points to a critical role for non-neutralizing antibody functions in protective immunity against a variety of pathogens, including HIV. Non-neutralizing antibody function is controlled by antibody constant domain interactions with Fc receptors, which itself is regulated via changes in antibody subclass/isotype selection or antibody glycosylation. This study specifically aimed to determine whether glycosylation of IgG is naturally tuned to target distinct pathogens or antigens and whether this activity can be actively modulated to direct antibody effector function. The study clearly demonstrates that the immune system naturally exploits unique IgG glycosylation profiles to target distinct pathogens and antigens and that this activity can be actively manipulated via vaccination. Moreover, because different vaccines drive unique glycosylation profiles, future studies that define the specific signals that control antibody glycosylation may lead to the generation of next-generation therapeutic interventions that can leverage and specifically direct the killing activity of the innate immune system, targeting HIV and beyond.