Influenza-Specific Antibody-Dependent Cellular Cytotoxicity: Toward a Universal Influenza Vaccine

Jegaskanda, Sinthujan; Reading, Patrick C.; Kent, Stephen J.

doi:10.4049/jimmunol.1400432

Cited by 116 publications

(144 citation statements)

References 75 publications

(90 reference statements)

Supporting

Mentioning

137

Contrasting

Order By: Relevance

“…However, extensive work by the Ravetch, Kent, and Ennis laboratories has demonstrated that cross-reactive antibodies are capable of eliciting ADCC against nonhomologous IAVs, and that the induction of ADCC by these antibodies might contribute to protection in vivo (22,(31)(32)(33)(34)(35)(36)(37). Furthermore, work by DiLillo et al (20) has demonstrated that ADCC induction by HA stalk-binding bnAbs is required for optimal protection on a lethal challenge of mice that received a passive transfer of a monoclonal HA stalk-binding bnAb.…”

Section: Discussionmentioning

confidence: 99%

“…Because induction of ADCC is known to play an important role in the protection against many viruses, including IAV and HIV (21,22), as well as in cancer immunotherapies (23), it will be important to consider the effects not only of antibody isotype, but also of specificity in the development of both novel vaccines and therapeutics. and C05 at equal concentrations resulted in inhibition of ADCC relative to CR8020 alone ( Fig.…”

Section: Significancementioning

confidence: 99%

See 1 more Smart Citation

Epitope specificity plays a critical role in regulating antibody-dependent cell-mediated cytotoxicity against influenza A virus

Tan

Mullarkey

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

165

163

View full text Add to dashboard Cite

The generation of strain-specific neutralizing antibodies against influenza A virus is known to confer potent protection against homologous infections. The majority of these antibodies bind to the hemagglutinin (HA) head domain and function by blocking the receptor binding site, preventing infection of host cells. Recently, elicitation of broadly neutralizing antibodies which target the conserved HA stalk domain has become a promising "universal" influenza virus vaccine strategy. The ability of these antibodies to elicit Fc-dependent effector functions has emerged as an important mechanism through which protection is achieved in vivo. However, the way in which Fc-dependent effector functions are regulated by polyclonal influenza virus-binding antibody mixtures in vivo has never been defined. Here, we demonstrate that interactions among viral glycoprotein-binding antibodies of varying specificities regulate the magnitude of antibody-dependent cell-mediated cytotoxicity induction. We show that the mechanism responsible for this phenotype relies upon competition for binding to HA on the surface of infected cells and virus particles. Nonneutralizing antibodies were poor inducers and did not inhibit antibody-dependent cell-mediated cytotoxicity. Interestingly, anti-neuraminidase antibodies weakly induced antibody-dependent cell-mediated cytotoxicity and enhanced induction in the presence of HA stalk-binding antibodies in an additive manner. Our data demonstrate that antibody specificity plays an important role in the regulation of ADCC, and that cross-talk among antibodies of varying specificities determines the magnitude of Fc receptor-mediated effector functions.T he discovery and ongoing characterization of broadly neutralizing antibodies (bnAbs) that bind to the hemagglutinin (HA) stalk domain of influenza A viruses (IAVs) has galvanized promising new efforts to generate a universal influenza virus vaccine (1). A number of studies have now firmly established that stalk-specific bnAbs, normally present in low quantities, can be boosted substantially in humans following exposure to HA subtypes with antigenically foreign head domains (2-8). Sequential vaccination of animals with chimeric HAs or with "headless" vaccine constructs have effectively recapitulated the boosting of bnAbs observed in humans after exposure to foreign HAs, and also are protective against heterologous and heterosubtypic IAV challenge (9-15). These strategies are now being tested as promising "universal" influenza virus vaccine candidates (16).Whereas traditional strain-specific antibodies neutralize virus by inhibiting receptor binding, stalk-binding bnAbs neutralize virus by distinct postbinding mechanisms (17). A direct comparison of in vitro neutralization has revealed that strain-specific mAbs that inhibit receptor binding tend to be more potent at neutralizing virus compared with monoclonal stalk-binding bnAbs (18, 19); however, this difference is minimized in the context of a polyclonal response (18). In addition to virus neutralization,...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Epitope specificity plays a critical role in regulating antibody-dependent cell-mediated cytotoxicity against influenza A virus

Tan

Mullarkey

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

165

163

View full text Add to dashboard Cite

show abstract

“…Few studies have evaluated the capacity of Abs produced along the anti-HCMV immune response to prevent viral replication by triggering NK cell-mediated recognition of HCMV-infected cells (38,39), despite previous evidences showing the contribution of NK cell-mediated ADCC to the control of other viruses (e.g., HIV and influenza) (40)(41)(42)(43)(44). Our study demonstrates that anti-HCMV Abs in immune sera can trigger an effective NK cell activation exceeding the low natural cytotoxicity levels against infected MRC5 cells.…”

Section: Nk Cell-mediated Ab-dependent Anti-hcmv Responsesmentioning

confidence: 99%

Antibody-Mediated Response of NKG2Cbright NK Cells against Human Cytomegalovirus

Costa‐García

Vera

Moraru³

et al. 2015

The Journal of Immunology

105

108

View full text Add to dashboard Cite

Human CMV (HCMV) infection promotes a variable and persistent expansion of functionally mature NKG2Cbright NK cells. We analyzed NKG2Cbright NK cell responses triggered by Abs from HCMV+ sera against HCMV-infected MRC5 fibroblasts. Specific Abs promoted the degranulation (i.e., CD107a expression) and the production of cytokines (TNF-α and IFN-γ) by a significant fraction of NK cells, exceeding the low natural cytotoxicity against HCMV-infected targets. NK cell–mediated Ab-dependent cell-mediated cytotoxicity was limited by viral Ag availability and HLA class I expression on infected cells early postinfection and increased at late stages, overcoming viral immunoevasion strategies. Moreover, the presence of specific IgG triggered the activation of NK cells against Ab-opsonized cell-free HCMV virions. As compared with NKG2A+ NK cells, a significant proportion of NKG2Cbright NK cells was FcεR γ-chain defective and highly responsive to Ab-driven activation, being particularly efficient in the production of antiviral cytokines, mainly TNF-α. Remarkably, the expansion of NKG2Cbright NK cells in HCMV+ subjects was related to the overall magnitude of TNF-α and IFN-γ cytokine secretion upon Ab-dependent and -independent activation. We show the power and sensitivity of the anti-HCMV response resulting from the cooperation between specific Abs and the NKG2Cbright NK-cell subset. Furthermore, we disclose the proinflammatory potential of NKG2Cbright NK cells, a variable that could influence the individual responses to other pathogens and tumors.

show abstract

“…Interaction between antibodies on the surface of influenza virus-infected cells and the Fcg-receptor(R) on natural killer (NK) cells results in the killing of those cells, a process called antibodydependent cellular cytotoxicity (ADCC) (reviewed in (Jegaskanda et al, 2014a). It has been suggested that the recruitment of these antibody-mediated Fc-FcgR-expressing effector cells by antibodies is a major in vivo mechanism of antibody-mediated protection from infection (DiLillo et al, 2014;Schmitz et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Influenza virus A(H1N1)2009 antibody-dependent cellular cytotoxicity in young children prior to the H1N1 pandemic

Mesman

Westerhuis

Hulscher

et al. 2016

Journal of General Virology

View full text Add to dashboard Cite

Pre-existing immunity played a significant role in protection during the latest influenza A virus H1N1 pandemic, especially in older age groups. Structural similarities were found between A(H1N1)2009 and older H1N1 virus strains to which humans had already been exposed. Broadly cross-reactive antibodies capable of neutralizing the A(H1N1)2009 virus have been implicated in this immune protection in adults. We investigated the serological profile of a group of young children aged 9 years (n=55), from whom paired blood samples were available, just prior to the pandemic wave (March 2009) and shortly thereafter (March 2010). On the basis of A(H1N1)2009 seroconversion, 27 of the 55 children (49 %) were confirmed to be infected between these two time points. Within the non-infected group of 28 children (51 %), high levels of seasonal antibodies to H1 and H3 HA1 antigens were detected prior to pandemic exposure, reflecting past infection with H1N1 and H3N2, both of which had circulated in The Netherlands prior to the pandemic. In some children, this reactivity coincided with specific antibody reactivity against A(H1N1)2009. While these antibodies were not able to neutralize the A(H1N1)2009 virus, they were able to mediate antibody-dependent cellular cytotoxicity (ADCC) in vitro upon interaction with the A(H1N1)2009 virus. This finding suggests that cross-reactive antibodies could contribute to immune protection in children via ADCC.

show abstract

Influenza-Specific Antibody-Dependent Cellular Cytotoxicity: Toward a Universal Influenza Vaccine

Cited by 116 publications

References 75 publications

Epitope specificity plays a critical role in regulating antibody-dependent cell-mediated cytotoxicity against influenza A virus

Epitope specificity plays a critical role in regulating antibody-dependent cell-mediated cytotoxicity against influenza A virus

Antibody-Mediated Response of NKG2Cbright NK Cells against Human Cytomegalovirus

Influenza virus A(H1N1)2009 antibody-dependent cellular cytotoxicity in young children prior to the H1N1 pandemic

Contact Info

Product

Resources

About