Background and aims HCMV reshapes NKR distribution, promoting an expansion of CD94/NKG2C+ NK and T cells. The dynamic of this process following primary HCMV infection is ill-defined. The role of NK cells in antiviral defence in preterm infants is unknown.

Aim To assess the dynamics of NKR expression in preterm infants with postnatal HCMV infection.

Methods NKR expression was analysed by flow cytometry at enrolment, 4 and 10 months in 19 initially HCMV-free infants (mean GA 34 w, range 32–36 w) and 6 infants with symptomatic postnatal HCMV infection (mean GA 29 w, range 26–41 w).

Results As compared to infants not infected at enrolment, those with symptomatic HCMV infection had increased proportions of NKG2C+ (40% vs 16%, p = 0.008) and KIR+ (60% vs 36%, p < 0.001) NK cells, but decreased percentages of NKG2A+ NK cells (60% vs 78%, p = 0.001). Increased proportions of NKG2C+, NKG2A+, LILRB1+, KIR+ and CD161⁺ T cells were also associated to HCMV infection (p < 0.05).

Four of the 7 initially HCMV-negative infants undergoing follow-up became asymptomatically HCMV-infected by 4 months and showed significant differences in the proportions of NKG2C+ and NKG2A+ NK cells in the second and third analyses with respect to patients remaining uninfected (p < 0.05).

NKG2C+ and KIR+ NK cell expansion in symptomatic infants persisted in the second and third samples (n = 5) and it was comparable to that observed in asymptomatic infection.

Conclusions HCMV infection is associated with a specific and persistent expansion of NKG2C+ NK cells. Innate immune response plays a role in HCMV infection control in preterm infants.