Date Published: March 16, 2016
Publisher: Public Library of Science
Author(s): Alison E. Mahan, Madeleine F. Jennewein, Todd Suscovich, Kendall Dionne, Jacquelynne Tedesco, Amy W. Chung, Hendrik Streeck, Maria Pau, Hanneke Schuitemaker, Don Francis, Patricia Fast, Dagna Laufer, Bruce D. Walker, Lindsey Baden, Dan H. Barouch, Galit Alter, Alexandra Trkola.
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.
Mounting evidence points to a critical role for non-neutralizing antibody effector function, such as antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and complement-dependent cytotoxicity (CDC), in protection against , and control of HIV , influenza , Ebola virus , and bacterial infections . Earlier work suggests that potent, long-lived antibody effector activity is driven by IgG1 antibodies , the dominant subclass in the blood . However, as all vaccinated and infected individuals ultimately produce IgG1 antibodies, it is unclear why some IgG1 responses provide protective immunity while others provide limited immunity at the same titers. While emerging data suggest that the co-selection of additional antibody subclasses, such as the most functional subclass, IgG3, may collaborate to direct more effective immune complex–based activity , IgG3 is cleared rapidly from the systemic circulation , arguing that sustained levels of some, but not other IgG1 antibodies may represent the critical determinant of protective immunity against HIV. Thus, defining how the immune system naturally tunes IgG1 represents a critical step for the development of more effective strategies to harness the immune system to prevent or control HIV infection.
Unlike subclass selection, which irreversibly changes the constant domain, antibody glycosylation represents a flexible and powerful mechanism by which the immune system naturally finely tunes antibody effector function. However, while significant changes in antibody glycosylation have been reported on bulk circulating antibodies in the setting of chronic inflammatory diseases  and on antigen-specific antibodies [15,32], it is still unclear whether the immune system naturally and selectively tunes antibody glycosylation in an antigen-specific manner. Here, we show differential glycosylation on distinct antigen- and pathogen-specific antibodies isolated from the same individuals (Fig 1), suggesting that the selection of antibody glycan profiles may be determined at the time of B cell priming as a means to specifically tune antibody effector activity to eliminate individual targets in an antigen/pathogen-appropriate manner. Moreover, we show that antibody glycosylation can be actively influenced via vaccination, overcoming different baseline circulating antibody glycome differences among vaccinees (Fig 2), to generate a specific antibody glycan profile within the vaccine-specific antibody subpopulation (Fig 3). Finally, distinct differences were observed in antibody glycan profiles among antibodies induced by different vaccines (vectored versus protein-only), highlighting the critical nature of distinct priming signals in directing the glycan profiles of antigen-specific antibodies (Fig 4). Given that antigen-specific antibodies represent only a small percent of the total circulating antibodies, which are composed of swarms of distinct epitope-specific antibodies, it is unlikely that antigen-specific antibody glycan shifts would influence the overall circulating glycome. However, differential antigen-specific antibody glycosylation clearly reflects differences in selective immune programming directed against distinct pathogens/antigens aimed at harnessing the broad Fc effector functional potential of the humoral immune response.