Modulation of Antibody-Mediated Effector Functions in Natural Killer Cells: Protective and Detrimental Effects in Infectious Diseases

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Background

NK cells mediate Fc-dependent antibody (Ab) functions thanks to the expression of Fc&gammaRIIIa/CD16, a type I, low affinity, activating receptor recognizing IgG-opsonized cells or multimeric IgG-containing immune complexes.

In human NK cells, CD16 associates with homo- or heterodimers of FcεRIγ and CD3ζ adaptors which connect the receptor to intracellular signaling pathways. CD16 engagement unleashes the full spectrum of NK cell functions against pathogens by promoting the killing of infected cells, as well as the production of pro-inflammatory cytokines and chemokines, through which they interface with and potentiate adaptive immune responses. Hence, the interaction of IgG with CD16 is critical in driving Ab-mediated antiviral immunity but also for the efficacy of vaccination-induced Abs and mAb-based regimens in infectious diseases.
Different from all the other innate immune cells which co-express the inhibitory Fc&gammaRIIb, NK cells are extremely sensitive to Ab-dependent activation; the amplitude of Fc-dependent functions is governed by several genetic and environmental factors affecting the avidity of Fc-CD16 interaction, as well as receptor signaling capability.

Host genetic factors impacting CD16 affinity and expression levels involve an FCGRIIIA single nucleotide polymorphism determining the presence of valine or phenylalanine at position 158. FCGRIIIA-V/V158 high-affinity variant commonly associated with improved biological response to mAb-based therapies and to Ab-mediated inflammatory signature.

The epigenetically regulated absence of FcεRIγ chain is the hallmark of a subset of long-lived NK cells called “memory”, expanding in the majority of HCMV-infected individuals. Although the absence of FcεRIγ in mature CD56dimCD16+ associates with a lower CD16 expression, it mediates enhanced responses, possibly due to its exclusive association to CD3ζ homodimer.

In the field of infectious diseases, Ab glycosylation is a newly appreciated post-translational modification with profound implications on IgG effector functions. IgG are glycosylated in their Fc domain at a conserved asparagine at position 297. Specifically, the removal of the core fucose greatly increases the affinity for CD16, resulting in enhanced functional outcomes. Individual differences in Fc glycosylation have been linked to both beneficial and detrimental pro-inflammatory outcomes and have received considerable attention in several infectious diseases. More recently, the correlation between COVID-19 disease severity and the presence of afucosylated anti-Spike IgG has been demonstrated, corroborating the idea that NK cells may participate to pro-inflammatory pathogenic immune responses. On the same line, a reduced inflammatory potential due to afucosylation and sialylation was evidenced in Abs elicited by mRNA vaccines. Finally, the COVID-19 pandemic has stimulated extensive efforts for the rapid development of anti-Sars-Cov2 mAbs with optimized Fc domain, indeed, preclinical models highlighted the improved clinical efficacy of defucosylated anti-Spike mAbs. The development of Fc-engineered mAbs became a new target for clinical intervention in therapeutic and preventive settings for other infectious diseases.
In this Research Topic, we aim to gather scientific contributions that address factors affecting the efficiency and the functional outcome of Fc-CD16 interaction focusing on the pathophysiological and clinical implications of infectious diseases.

Original Research, Perspective, Review, Systematic Review, and Technology will be accepted in this Research Topic.

Keywords: Infectious Disease, Natural Killer cells, antibody

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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