In Utero Activation of NK Cells in Congenital CMV Infection

Abstract

Background: Congenital cytomegalovirus (CMV) infection is the most common infectious cause of birth defects and neurological damage in newborns. Despite a well-established role for NK cells in control of CMV infection in older children and adults, it remains unknown whether fetal NK cells can sense and respond to CMV infection acquired in utero. Methods: Here, we investigate the impact of congenital CMV infection on the neonatal NK cell repertoire by assessing the frequency, phenotype, and functional profile of NK cells in cord blood samples from newborns with congenital CMV and from uninfected controls enrolled in a birth cohort of Ugandan mothers and infants. Results: We find that neonatal NK cells from congenitally CMV infected newborns show increased expression of cytotoxic mediators, signs of maturation and activation, and an expansion of mature CD56-negative NK cells, an NK cell subset associated with chronic viral infections in adults. Activation was particularly prominent in NK cell subsets expressing the Fcγ receptor CD16, indicating a role for antibody-mediated immunity against CMV in utero. Conclusion: These findings demonstrate that NK cells can be activated in utero and suggest that NK cells may be an important component of the fetal and infant immune response against CMV.

ADCC-activating antibodies correlate with protection against congenital human cytomegalovirus infection

“…Nevertheless, cord blood sera ADCC responses were strongly associated with protection against transmission and anti-UL16 IgG was highly transferred to uninfected infants. Vaaben et al also recently observed that cord blood NK cells expressing FcγRIII/CD16 are expanded in utero following cCMV infection (45,46). Taken together, these studies suggest that maternal ADCC-activating antibodies transferred across the placenta and fetal NK cells expressing FcγRIII may synergize to defend against HCMV (45,46).…”

“…Vaaben et al also recently observed that cord blood NK cells expressing FcγRIII/CD16 are expanded in utero following cCMV infection (45,46). Taken together, these studies suggest that maternal ADCC-activating antibodies transferred across the placenta and fetal NK cells expressing FcγRIII may synergize to defend against HCMV (45,46). Therefore, strategies to enhance placental transfer of these potentially protective antibodies through Fc-engineering and to engage fetal and/or neonatal innate immune cells in Fc-mediated immunity should be explored.…”