A Human Anti-M2 Antibody Mediates Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) and Cytokine Secretion by Resting and Cytokine-Preactivated Natural Killer (NK) Cells

Abstract

The highly conserved matrix protein 2 (M2) is a good candidate for the development of a broadly protective influenza vaccine that induces long-lasting immunity. In animal models, natural killer (NK) cells have been proposed to play an important role in the protection provided by M2-based vaccines through a mechanism of antibody-dependent cell-mediated cytotoxicity (ADCC). We investigated the ability of the human anti-M2 Ab1-10 monoclonal antibody (mAb) to activate human NK cells. They mediated ADCC against M2-expressing cells in the presence of Ab1-10 mAb. Furthermore, NK cell pro-inflammatory cytokine and chemokine secretion is also enhanced when Ab1-10 mAb is present. We also generated cytokine-preactivated NK cells and showed that they still displayed increased effector functions in the presence of Ab1-10 mAb. Thus, our study has demonstrated that human resting and cytokine-preactivated NK cells may have a very important role in the protection provided by anti-M2 Abs.

Generation and Protective Ability of Influenza Virus–Specific Antibody-Dependent Cellular Cytotoxicity in Humans Elicited by Vaccination, Natural Infection, and Experimental Challenge

“…We speculate that these antibodies are generated early in life and are expanded by infection and vaccination. We have not considered ADCC-Abs to other viral components, including M proteins, although antibodies to M2 protein have been shown to mediate their activity through ADCC [21,22]. However, the contribution of such cross-reactive ADCC-Abs to protection in humans is still unclear and requires further investigation.…”

The protective potential of Fc‐mediated antibody functions against influenza virus and other viral pathogens

“…Prophylactic and therapeutic treatment of mice with a human M2e‐specific mAb (Z3G1) reduced viral load in the lungs and protected mice from lethal influenza virus challenge through FcγR‐ and complement‐dependent mechanisms . Another human M2e mAb (Ab1‐10) activated NK cells and killed influenza‐infected as well as matrix 2‐expressing cells in vitro . More conserved influenza antigens may be important targets for Fc‐functional antibodies and could inform the development of universal influenza vaccines and immunotherapies.…”

Development of a Universal Influenza Vaccine

“…Many other virus-like particle methods have now been employed with M2e (72)(73)(74). The protection elicited by Abs to M2e are not sterilizing and instead bind to the surface of virus-infected cells, most likely acting through Ab-dependent cellular cytotoxicity (75)(76)(77)(78). The conservation and cross-protective properties of M2e are an exciting aspect of influenza vaccination improvement and will most likely prove indispensable for the development of a universal influenza vaccine.…”