Harnessing the Fc Region: Antibody Fc Modulation in Infection and Pregnancy

Abstract

Antibody-mediated responses to pathogens and infected cells are essential for most effective immune responses. While the Fab domain of antibodies is critical for binding and neutralizing pathogens, the antibody Fc domain mediates important non-neutralizing functions through interactions with Fc-receptors on innate immune cells. Thus, the Fc-functionality of antibodies bridges the innate and adaptive systems, allowing the innate immune system to efficiently harness the specificity of the adaptive immune response. While Fab-mediated neutralization has long been viewed as the dominant mechanism of antibody-mediated immunity, there is a growing appreciation for the role of non-neutralizing functions of antibodies. Particularly in HIV research, where decades of intensive study have yet to yield an effective vaccine, emerging roles for alternate, Fc-functionality-based, antibody responses are gaining attention for their potential importance in protection and cure strategies. Modulation of the Fc and Fab characteristics of antibodies is important not only in infection and vaccine responses, but also in other immunologically distinct states, including pregnancy. This work will explore changes in antibody Fc effector functions during infection and vaccination in the contexts of HIV/SIV and pregnancy, delving into both the importance of the antibody Fc for the potential anti-pathogen activity of antibodies, but also more broadly into the immunoregulatory properties of the antibody Fc. We show that antibody Fc-glycosylation is directable via vaccination, and that the formation of larger immune complexes facilitates a more efficacious, Fc-mediated, immune response to SIV. Furthermore, we show that Fc-polyfunctionality may be important in the early control of HIV infection. We also extend the research on Fc-functionality to the realm of pregnancy, showing that vaccines elicit a different antibody response during pregnancy, and, importantly, that antibody Fc characteristics drive the selective transfer of antibodies across the placenta. Collectively, these data offer insights into the regulation of Fc-functionality in different immune conditions and underline the importance of considering the antibody Fc when studying antibody-mediated immune responses or designing antibody-based therapeutics. These data have important implications for designing novel vaccines, whether for HIV, in pregnancy, or in other contexts, that harness the power of the antibody Fc to elicit robust immune responses.