ADCC-activating antibodies correlate with decreased risk of congenital human cytomegalovirus transmission
Eleanor C. Semmes, Itzayana G. Miller, Nicole Rodgers, Caroline T. Phan, Jillian H. Hurst, Kyle M. Walsh, Richard J. Stanton, Justin Pollara, Sallie R. Permar
Eleanor C. Semmes, Itzayana G. Miller, Nicole Rodgers, Caroline T. Phan, Jillian H. Hurst, Kyle M. Walsh, Richard J. Stanton, Justin Pollara, Sallie R. Permar
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Research Article Immunology Infectious disease

ADCC-activating antibodies correlate with decreased risk of congenital human cytomegalovirus transmission

Abstract

Human cytomegalovirus (HCMV) is the most common vertically transmitted infection worldwide, yet there are no vaccines or therapeutics to prevent congenital HCMV (cCMV) infection. Emerging evidence indicates that antibody Fc effector functions may be a previously underappreciated component of maternal immunity against HCMV. We recently reported that antibody-dependent cellular phagocytosis (ADCP) and IgG activation of FcγRI/FcγRII were associated with protection against cCMV transmission, leading us to hypothesize that additional Fc-mediated antibody functions may be important. In this same cohort of HCMV-transmitting (n = 41) and nontransmitting (n = 40) mother-infant dyads, we report that higher maternal sera antibody–dependent cellular cytotoxicity (ADCC) activation is also associated with lower risk of cCMV transmission. We investigated the relationship between ADCC and IgG responses against 9 viral antigens and found that ADCC activation correlated most strongly with sera IgG binding to the HCMV immunoevasin protein UL16. Moreover, we determined that higher UL16-specific IgG binding and FcγRIII/CD16 engagement were associated with the greatest risk reduction in cCMV transmission. Our findings indicate that ADCC-activating antibodies against targets such as UL16 may represent an important protective maternal immune response against cCMV infection that can guide future HCMV correlates studies and vaccine or antibody-based therapeutic development.

Authors

Eleanor C. Semmes, Itzayana G. Miller, Nicole Rodgers, Caroline T. Phan, Jillian H. Hurst, Kyle M. Walsh, Richard J. Stanton, Justin Pollara, Sallie R. Permar

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Figure 6

Anti-UL16 IgG activates NK cell ADCC in HCMV nontransmitting pregnancies.

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Anti-UL16 IgG activates NK cell ADCC in HCMV nontransmitting pregnancies...
(A–D) ADCC activation was quantified as NK cell degranulation (% CD107a+ NK cells; gating strategy in Supplemental Figure 2) against fibroblasts infected with HCMV (A and B) or transduced with a recombinant adenovirus (rAd) expressing UL16 or a control rAd (C and D). Anti-UL16 IgG binding was measured with a binding antibody multiple assay. (A and B) Scatterplots of maternal sera responses from transmitting (red circles, n = 41) and nontransmitting (blue diamonds, n = 40) dyads. (A) Spearman correlation between anti-HCMV ADCC and anti-UL16 IgG levels. (B) Spearman correlation between anti-HCMV ADCC and anti-UL16 IgG binding to FcγRIII high-affinity V158 and low-affinity F158 variants. (C and D) NK cell degranulation against UL16rRAd (purple) and control rAd (black) using Cytogam (positive control), seronegative sera (negative control), and a limited subset of maternal sera samples (n = 6) selected based on sera volume availability. Dots represent biological replicates tested at 1:10 and 1:50 sera dilution. Serum samples with a range of representative anti–UL16 IgG FcγRIII binding responses were included. (E) Hypothetical model demonstrating proposed role for anti-UL16 IgG binding to FcγRIII in mediating NK cell ADCC against HCMV-infected cells. (E) FDR-corrected P values reported for Mann-Whitney U test. **P < 0.01, ***P < 0.001.