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 1

HCMV-specific ADCC and FcγRIII/CD16 activating antibodies in HCMV transmitting versus nontransmitting mother-infant dyads.

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HCMV-specific ADCC and FcγRIII/CD16 activating antibodies in HCMV transm...
HCMV-specific ADCC and FcγRIII IgG activation was measured using maternal (M) and cord blood (CB) sera from HCMV transmitting (red circles, n = 41) and nontransmitting (blue diamonds, n = 40) mother-infant dyads. Antibody responses were compared between and within dyads. (A) NK cell degranulation (% CD107a+ NK cells; gating strategy in Supplemental Figure 2) was quantified as a read-out of ADCC using a flow-based assay. Primary NK cells were isolated from PBMCs by negative selection with magnetic beads prior to coincubation with HCMV-infected and mock-infected cells. Cytogam (light green), HCMV seropositive (light and dark blue), and HCMV seronegative (gray) sera samples were included as controls. (B) HCMV-specific antibody ADCC responses in transmitting and nontransmitting dyads. (C) Flow cytometry of FcγR-CD3ζ BW cells showing unstained (red), isotype control (orange), anti-FcγRI/CD64 (light green), anti-FcγRII/CD32 (blue), and anti-FcγRIII/CD16 (purple) PE–conjugated antibody staining. (D) Anti–HCMV IgG FcγRIII activation in transmitting and nontransmitting dyads. (E) Scatterplots showing Spearman correlations between HCMV-specific ADCC and FcγRIII IgG activation. IgG transfer ratio equals paired cord blood/maternal sera responses. Horizontal black bars denote median. (A and D) FDR-corrected P values for Mann-Whitney U test (left) or Wilcoxon signed-rank test (right). *P < 0.05, **P < 0.01, ***P < 0.001.